Slab Geometry and Upper Mantle Flow Patterns in the Central Mediterranean From 3D Anisotropic P-Wave Tomography.

We present the first three-dimensional (3D) anisotropic teleseismic P-wave tomography model of the upper mantle covering the entire Central Mediterranean. Compared to isotropic tomography, it is found that including the magnitude, azimuth, and, importantly, dip of seismic anisotropy in our inversions simplifies isotropic heterogeneity by reducing the magnitude of slow anomalies while yielding anisotropy patterns that are consistent with regional tectonics. The isotropic component of our preferred tomography model is dominated by numerous fast anomalies associated with retreating, stagnant, and detached slab segments. In contrast, relatively slower mantle structure is related to slab windows and the opening of back-arc basins. To better understand the complexities in slab geometry and their relationship to surface geological phenomenon, we present a 3D reconstruction of the main Central Mediterranean slabs down to 700 km based on our anisotropic model. P-wave seismic anisotropy is widespread in the Central Mediterranean upper mantle and is strongest at 200-300 km depth. The anisotropy patterns are interpreted as the result of asthenospheric material flowing primarily horizontally around the main slabs in response to pressure exerted by their mid-to-late Cenezoic horizontal motion, while sub-vertical anisotropy possibly reflects asthenospheric entrainment by descending lithosphere. Our results highlight the importance of anisotropic P-wave imaging for better constraining regional upper mantle geodynamics.

Testosterone positively regulates vagina NO-induced relaxation: an experimental study in rats.

PURPOSE: Female sexual response involves a complex interplay between neurophysiological mechanisms and the nitric oxide (NO)-mediated relaxation of clitoris and vagina. The aim of this study was to evaluate sex steroids regulation of the relaxant pathway in vagina, using a validated animal model. METHODS: Subgroups of OVX Sprague-Dawley rats were treated with 17ß-estradiol, testosterone, or testosterone and letrozole, and compared with a group of intact animals. Masson's trichrome staining was performed for morphological evaluation of the distal vaginal wall, in vitro contractility studies investigated the effect of OVX and in vivo treatments on vaginal smooth muscle activity. RNA from vaginal tissue was analyzed by semi-quantitative RT-PCR. RESULTS: Immunohistochemical analysis showed that OVX induced epithelial and smooth muscle structural atrophy, testosterone and testo + letrozole increased the muscle bundles content and organization without affecting the epithelium while 17ß-estradiol mediated the opposite effects. In vitro contractility studies were performed on noradrenaline pre-contracted vaginal strips from each experimental group. Acetylcholine (0.001-10 µM) stimulation induced a concentration-dependent relaxation, significantly reduced by NO-synthase inhibitor L-NAME and by guanylate cyclase inhibitor ODQ. OVX resulted in a decreased responsiveness to acetylcholine, restored by testosterone, with or without letrozole, but not by 17ß-estradiol. OVX sensitivity to the NO-donor SNP was higher than in the control. Vardenafil, a PDE5 inhibitor, enhanced SNP effect in OVX + testosterone as well as in control, as supported by RNA expression analysis. CONCLUSIONS: Our study demonstrates that testosterone improves the NO-mediated smooth muscle vaginal cells relaxation confirming its role in maintaining the integrity of muscular relaxant machinery.

Uppermost crustal structure regulates the flow of the Greenland Ice Sheet.

The flow of the Greenland Ice Sheet is controlled by subglacial processes and conditions that depend on the geological provenance and temperature of the crust beneath it, neither of which are adequately known. Here we present a seismic velocity model of the uppermost 5 km of the Greenlandic crust. We show that slow velocities in the upper crust tend to be associated with major outlet glaciers along the ice-sheet margin, and elevated geothermal heat flux along the Iceland hotspot track inland. Outlet glaciers particularly susceptible to basal slip over deformable subglacial sediments include Jakobshavn, Helheim and Kangerdlussuaq, while geothermal warming and softening of basal ice may affect the onset of faster ice flow at Petermann Glacier and the Northeast Greenland Ice Stream. Interactions with the solid earth therefore control the past, present and future dynamics of the Greenland Ice Sheet and must be adequately explored and implemented in ice sheet models.

Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model.

PURPOSE: Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. METHODS: Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson's trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. RESULTS: Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. CONCLUSIONS: Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.

Atlantic and Mediterranean populations of the widespread serpulid Ficopomatus enigmaticus: Developmental responses to carbon nanotubes.

Ficopomatus enigmaticus was adopted as model species for ecotoxicological bioassay, with its larval development as endpoint. Two different populations of the same species, collected in areas far from each other (Mediterranean Sea and Atlantic Ocean), were exposed to multi-walled carbon nanotubes, a class of emerging pollutants with a constantly increasing relevance in the landscape of nanomaterials production. Moreover, a molecular analysis based on Cyt b amplification and sequencing, was carried out to confirm that both populations belong to the same species. The aim of the present work was to strengthen existing results about F. enigmaticus relevance in ecotoxicological bioassays, adding the variable of population effect. For both populations the concentration-response curve of effect at different toxicant concentrations was similar and, at certain concentrations, overlapping, confirming the ecological relevance of the assay. These results posed an interesting acceptance on the introduction of this species as model in ecotoxicological bioassay scenery, underlining the relevance of a widespread wild species to compare effects of chemicals and environmental samples over large distances using the same bioassay.

Knowing me, knowing you: theory of mind in AI.

Artificial intelligence has dramatically changed the world as we know it, but is yet to fully embrace 'hot' cognition, i.e., the way an intelligent being's thinking is affected by their emotional state. Artificial intelligence encompassing hot cognition will not only usher in enhanced machine-human interactions, but will also promote a much needed ethical approach. Theory of Mind, the ability of the human mind to attribute mental states to others, is a key component of hot cognition. To endow machines with (limited) Theory of Mind capabilities, computer scientists will need to work closely with psychiatrists, psychologists and neuroscientists. They will need to develop new models, but also to formally define what problems need to be solved and how the results should be assessed.

Systematic review and literature appraisal on methodology of conducting and reporting critical-care echocardiography studies: a report from the European Society of Intensive Care Medicine PRICES expert panel.

BACKGROUND: The echocardiography working group of the European Society of Intensive Care Medicine recognized the need to provide structured guidance for future CCE research methodology and reporting based on a systematic appraisal of the current literature. Here is reported this systematic appraisal. METHODS: We conducted a systematic review, registered on the Prospero database. A total of 43 items of common interest to all echocardiography studies were initially listed by the experts, and other "topic-specific" items were separated into five main categories of interest (left ventricular systolic function, LVSF n = 15, right ventricular function, RVF n = 18, left ventricular diastolic function, LVDF n = 15, fluid management, FM n = 7, and advanced echocardiography techniques, AET n = 17). We evaluated the percentage of items reported per study and the fraction of studies reporting a single item. RESULTS: From January 2000 till December 2017 a total of 209 articles were included after systematic search and screening, 97 for LVSF, 48 for RVF, 51 for LVDF, 36 for FM and 24 for AET. Shock and ARDS were relatively common among LVSF articles (both around 15%) while ARDS comprised 25% of RVF articles. Transthoracic echocardiography was the main echocardiography mode, in 87% of the articles for AET topic, followed by 81% for FM, 78% for LVDF, 70% for LVSF and 63% for RVF. The percentage of items per study as well as the fraction of study reporting an item was low or very low, except for FM. As an illustration, the left ventricular size was only reported by 56% of studies in the LVSF topic, and half studies assessing RVF reported data on pulmonary artery systolic pressure. CONCLUSION: This analysis confirmed sub-optimal reporting of several items listed by an expert panel. The analysis will help the experts in the development of guidelines for CCE study design and reporting.

Therapeutic effects of the selective farnesoid X receptor agonist obeticholic acid in a monocrotaline-induced pulmonary hypertension rat model.

BACKGROUND: Activation of the farnesoid X receptor (FXR), a member of the nuclear receptor steroid superfamily, leads to anti-inflammatory and anti-fibrotic effects in several tissues, including the lung. We have recently demonstrated a protective effect of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) in rat models of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and bleomycin-induced pulmonary fibrosis. The aim of the present study was to investigate whether the positive effects of OCA treatment could be exerted also in established MCT-induced PAH, i.e., starting treatment 2 weeks after MCT administration. METHODS: Rats with MCT-induced PAH were treated, 2 weeks after MCT administration, with OCA or tadalafil for two additional weeks. Pulmonary functional tests were performed at week 2 (before treatment) and four (end of treatment). At the same time points, lung morphological features and expression profile of genes related to smooth muscle relaxation/contraction and tissue remodeling were also assessed. RESULTS: 2 weeks after MCT-induced injury, the treadmill resistance (a functional parameter related to pulmonary hypertension) was significantly decreased. At the same time point, we observed right ventricular hypertrophy and vascular remodeling, with upregulation of genes related to inflammation. At week 4, we observed a further worsening of the functional and morphological parameters, accompanied by dysregulation of inflammatory and extracellular matrix markers mRNA expression. Administration of OCA (3 or 10 mg/kg/day), starting 2 weeks after MCT-induced injury, significantly improved pulmonary function, effectively normalizing the exercise capacity. OCA also reverted most of the lung alterations, with a significant reduction of lung vascular wall thickness, right ventricular hypertrophy, and restoration of the local balance between relaxant and contractile pathways. Markers of remodeling pathways were also normalized by OCA treatment. Notably, results with OCA treatment were similar, or even superior, to those obtained with tadalafil, a recently approved treatment for pulmonary hypertension. CONCLUSIONS: The results of this study demonstrate a significant therapeutic effect of OCA in established MCT-induced PAH, improving exercise capacity associated with reduction of right ventricular hypertrophy and lung vascular remodeling. Thus, OCA dosing in a therapeutic protocol restores the balance between relaxant and contractile pathways in the lung, promoting cardiopulmonary protective actions in MCT-induced PAH.

Therapeutic effects of obeticholic acid (OCA) treatment in a bleomycin-induced pulmonary fibrosis rat model.

PURPOSE: We recently demonstrated a protective effect of the farnesoid X receptor agonist obeticholic acid (OCA) in rat models of bleomycin-induced pulmonary fibrosis (PF). Aim of the present study was to investigate whether the positive effects of OCA treatment are apparent also on ongoing bleomycin-induced PF, i.e., after 2 weeks of bleomycin administration. METHODS: Bleomycin-induced PF rats were treated 2 weeks after bleomycin administration with OCA or pirfenidone for two additional weeks. Pulmonary function test was performed at 2 and 4 weeks in all experimental groups. At the same time points, lung morphological features and mRNA expression profile of genes related to fibrosis, inflammation and epithelial-mesenchymal transition were also assessed. RESULTS: After 2 weeks, bleomycin significantly increased the pressure at the airway opening (PAO), a functional parameter related to fibrosis-induced lung stiffness, and induced diffuse lung interstitium fibrosis, with upregulation of inflammation (IL1ß, MCP1) and tissue remodeling (COL1A1, COL3A1, ET1, MMP7, PDGFa, αSMA, SNAI1) markers. At week four, a further increase of lung fibrosis and PAO was observed, accompanied by upregulation of extracellular matrix-related mRNA expression. OCA administration, even after the establishment of PF, significantly improved pulmonary function, normalizing PAO, and reverted the bleomycin-induced lung alterations, with significant reduction of markers of inflammation (CD206, COX2, HIF1, IL1ß, MCP1), epithelial proliferation (CTGF, PDGFa) and fibrosis (COL1A1, COL3A1, ET1, FN1, MMPs, αSMA, SNAIs, TGFß1, TIMPs). Results with OCA were similar or superior to those obtained with pirfenidone. CONCLUSIONS: In conclusion, our results demonstrate a significant therapeutic effect of OCA in already established PF.

Correction to: Practical approach to diastolic dysfunction in light of the new guidelines and clinical applications in the operating room and in the intensive care.

In the original article [1], the authors noticed a typographical error in Figure 2. The top left box should have included "E/A <0.8 and E <50 cm/s". Please see below the corrected figure.

Practical approach to diastolic dysfunction in light of the new guidelines and clinical applications in the operating room and in the intensive care.

There is growing evidence both in the perioperative period and in the field of intensive care (ICU) on the association between left ventricular diastolic dysfunction (LVDD) and worse outcomes in patients. The recent American Society of Echocardiography and European Association of Cardiovascular Imaging joint recommendations have tried to simplify the diagnosis and the grading of LVDD. However, both an often unknown pre-morbid LV diastolic function and the presence of several confounders-i.e., use of vasopressors, positive pressure ventilation, volume loading-make the proposed parameters difficult to interpret, especially in the ICU. Among the proposed parameters for diagnosis and grading of LVDD, the two tissue Doppler imaging-derived variables e' and E/e' seem most reliable. However, these are not devoid of limitations. In the present review, we aim at rationalizing the applicability of the recent recommendations to the perioperative and ICU areas, discussing the clinical meaning and echocardiographic findings of different grades of LVDD, describing the impact of LVDD on patients' outcomes and providing some hints on the management of patients with LVDD.

Effects of resuscitation with human albumin 5%, hydroxyethyl starch 130/0.4 6%, or crystalloid on kidney damage in an ovine model of septic shock.

BACKGROUND: Colloid solutions have been associated with kidney dysfunction in septic animals and humans. The present study investigated the influence of resuscitation with human albumin (HA) 5%, hydroxyethyl starch (HES) 130/0.4 6%, and balanced crystalloids on ultrastructural kidney damage, kidney function, and survival in a model of ovine septic shock. METHODS: After induction of peritoneal septic shock, animals were randomised to one of the following groups: (1) HA 5%, (2) HES 130/0.4 6%, (3) balanced crystalloid, and (4) control (each n=10). Causal therapy included re-laparotomy, peritoneal lavage, and antimicrobial therapy. Sequential kidney biopsies were obtained for the assessment of the electron microscopic tubular injury (EMTI) score. RESULTS: Serum creatinine and urea were highest in the control group, and there were no differences between the intervention groups. Cumulative diuresis was significantly higher in the HA group [1.0 ml kg-1 h-1 (0.6; 1.2)] compared with control [0.7 ml kg-1 h-1 (0.6; 0.9), P<0.05]. Creatinine clearance was highest in the HA and crystalloid groups. Ultrastructural kidney damage was highest in the control group [EMTI score 7.8 (6.7; 9.0)] without differences between intervention groups. Survival was 100% in the colloid groups vs 90% (crystalloid) and 60% (control, all P<0.05). CONCLUSION: In an ovine model of septic shock, kidney function and cumulative diuresis were preserved in the 5% albumin and crystalloid resuscitation groups, whereas HES 130/0.4 6% resulted in diminished creatinine clearance. Differences in kidney function between resuscitation fluids could not be explained by differences in ultrastructural kidney damage. CLINICAL TRIAL REGISTRATION: 84-02.04.2011.A300.

Continuing chronic beta-blockade in the acute phase of severe sepsis and septic shock is associated with decreased mortality rates up to 90 days.

BACKGROUND: There is growing evidence that beta-blockade may reduce mortality in selected patients with sepsis. However, it is unclear if a pre-existing, chronic oral beta-blocker therapy should be continued or discontinued during the acute phase of severe sepsis and septic shock. METHODS: The present secondary analysis of a prospective observational single centre trial compared patient and treatment characteristics, length of stay and mortality rates between adult patients with severe sepsis or septic shock, in whom chronic beta-blocker therapy was continued or discontinued, respectively. The acute phase was defined as the period ranging from two days before to three days after disease onset. Multivariable Cox regression analysis was performed to compare survival outcomes in patients with pre-existing chronic beta-blockade. RESULTS: A total of 296 patients with severe sepsis or septic shock and pre-existing, chronic oral beta-blocker therapy were included. Chronic beta-blocker medication was discontinued during the acute phase of sepsis in 129 patients and continued in 167 patients. Continuation of beta-blocker therapy was significantly associated with decreased hospital (P=0.03), 28-day (P=0.04) and 90-day mortality rates (40.7% vs 52.7%; P=0.046) in contrast to beta-blocker cessation. The differences in survival functions were validated by a Log-rank test (P=0.01). Multivariable analysis identified the continuation of chronic beta-blocker therapy as an independent predictor of improved survival rates (HR = 0.67, 95%-CI (0.48, 0.95), P=0.03). CONCLUSIONS: Continuing pre-existing chronic beta-blockade might be associated with decreased mortality rates up to 90 days in septic patients.

Renal Allograft Survival in Nonhuman Primates Infused With Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells.

Systemic administration of autologous regulatory dendritic cells (DCreg; unpulsed or pulsed with donor antigen [Ag]), prolongs allograft survival and promotes transplant tolerance in rodents. Here, we demonstrate that nonhuman primate (NHP) monocyte-derived DCreg preloaded with cell membrane vesicles from allogeneic peripheral blood mononuclear cells induce T cell hyporesponsiveness to donor alloantigen (alloAg) in vitro. These donor alloAg-pulsed autologous DCreg (1.4-3.6 × 106 /kg) were administered intravenously, 1 day before MHC-mismatched renal transplantation to rhesus monkeys treated with costimulation blockade (cytotoxic T lymphocyte Ag 4 immunoglobulin [CTLA4] Ig) and tapered rapamycin. Prolongation of graft median survival time from 39.5 days (no DCreg infusion; n = 6 historical controls) and 29 days with control unpulsed DCreg (n = 2), to 56 days with donor Ag-pulsed DCreg (n = 5) was associated with evidence of modulated host CD4+ and CD8+ T cell responses to donor Ag and attenuation of systemic IL-17 production. Circulating anti-donor antibody (Ab) was not detected until CTLA4 Ig withdrawal. One monkey treated with donor Ag-pulsed DCreg rejected its graft in association with progressively elevated anti-donor Ab, 525 days posttransplant (160 days after withdrawal of immunosuppression). These findings indicate a modest but not statistically significant beneficial effect of donor Ag-pulsed autologous DCreg infusion on NHP graft survival when administered with a minimal immunosuppressive drug regimen.

Heart rate reduction with esmolol is associated with improved arterial elastance in patients with septic shock: a prospective observational study.

PURPOSE: Ventricular-arterial (V-A) decoupling decreases myocardial efficiency and is exacerbated by tachycardia that increases static arterial elastance (Ea). We thus investigated the effects of heart rate (HR) reduction on Ea in septic shock patients using the beta-blocker esmolol. We hypothesized that esmolol improves Ea by positively affecting the tone of arterial vessels and their responsiveness to HR-related changes in stroke volume (SV). METHODS: After at least 24 h of hemodynamic optimization, 45 septic shock patients, with an HR ≥95 bpm and requiring norepinephrine to maintain mean arterial pressure (MAP) ≥65 mmHg, received a titrated esmolol infusion to maintain HR between 80 and 94 bpm. Ea was calculated as MAP/SV. All measurements, including data from right heart catheterization, echocardiography, arterial waveform analysis, and norepinephrine requirements, were obtained at baseline and at 4 h after commencing esmolol. RESULTS: Esmolol reduced HR in all patients and this was associated with a decrease in Ea (2.19 ± 0.77 vs. 1.72 ± 0.52 mmHg l(-1)), arterial dP/dt max (1.08 ± 0.32 vs. 0.89 ± 0.29 mmHg ms(-1)), and a parallel increase in SV (48 ± 14 vs. 59 ± 18 ml), all p < 0.05. Cardiac output and ejection fraction remained unchanged, whereas norepinephrine requirements were reduced (0.7 ± 0.7 to 0.58 ± 0.5 µg kg(-1) min(-1), p < 0.05). CONCLUSIONS: HR reduction with esmolol effectively improved Ea while allowing adequate systemic perfusion in patients with severe septic shock who remained tachycardic despite standard volume resuscitation. As Ea is a major determinant of V-A coupling, its reduction may contribute to improving cardiovascular efficiency in septic shock.

Predictors of outcome in ICU patients with septic shock caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae.

The aim of this study was to identify factors associated with mortality in intensive care unit patients with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) septic shock. A retrospective analysis of intensive care unit patients with KPC-Kp infection and septic shock observed in a large teaching hospital from November 2010 to December 2014 was performed. A total of 111 patients were included in the study. The most frequent source of infection was unknown-focus bacteraemia in 53 patients (47.7%). The rate of resistance to colistin was 51.3%; 30-day mortality was reported for 44 patients (39.6%). Surviving patients were more frequently treated with an initial therapy (within 24 hours) including two or more antibiotics displaying in vitro activity against the isolated KPC-Kp strain (41.8 vs. 18.1%, p 0.01) and were also more likely to receive a definitive therapy including two or more in vitro active antibiotics (85.1 vs. 15.9%, p <0.001). Cox regression analysis revealed that a colistin-containing antibiotic regimen (hazard ratio (HR) 0.21, confidence interval (CI) 95% 0.05-0.72, p <0.001), use of two or more in vitro active antibiotics as definite therapy (HR 0.08, CI 95% 0.02-0.21, p <0.001) and control of removable source of infection (HR 0.14, CI 95% 0.04-0.25, p <0.001) were associated with favourable outcome; colistin resistance (HR 8.09, CI 95% 3.14-11.23, p 0.001) and intra-abdominal source of infection (HR 2.92, CI 95% 2.11-4.12, p 0.002) were associated with death. In conclusion, use of a definitive therapy with at least two antibiotics displaying in vitro activity against the KPC-Kp isolates was the most important determinant of favourable outcome, whilst isolation of colistin-resistant strains was associated with death in septic patients with KPC-Kp infection.

Oxidative stress in myelin sheath: The other face of the extramitochondrial oxidative phosphorylation ability.

Oxidative phosphorylation (OXPHOS) is not only the main source of ATP for the cell, but also a major source of reactive oxygen species (ROS), which lead to oxidative stress. At present, mitochondria are considered the organelles responsible for the OXPHOS, but in the last years we have demonstrated that it can also occur outside the mitochondrion. Myelin sheath is able to conduct an aerobic metabolism, producing ATP that we have hypothesized is transferred to the axon, to support its energetic demand. In this work, spectrophotometric, cytofluorimetric, and luminometric analyses were employed to investigate the oxidative stress production in isolated myelin, as far as its respiratory activity is concerned. We have evaluated the levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), markers of lipid peroxidation, as well as of hydrogen peroxide (H2O2), marker of ROS production. To assess the presence of endogenous antioxidant systems, superoxide dismutase, catalase, and glutathione peroxidase activities were assayed. The effect of certain uncoupling or antioxidant molecules on oxidative stress in myelin was also investigated. We report that isolated myelin produces high levels of MDA, 4-HNE, and H2O2, likely through the pathway composed by Complex I-III-IV, but it also contains active superoxide dismutase, catalase, and glutathione peroxidase, as antioxidant defense. Uncoupling compounds or Complex I inhibitors increase oxidative stress, while antioxidant compounds limit ROS generation. Data may shed new light on the role of myelin sheath in physiology and pathology. In particular, it can be presumed that the axonal degeneration associated with myelin loss in demyelinating diseases is related to oxidative stress caused by impaired OXPHOS.

Clinical implications of basic science discoveries: nociceptive neurons as targets to control immunity--potential relevance for transplantation.

Increasing evidence indicates the existence of a complex cross-regulation between the most important biosensors of the human body: The immune and nervous systems. Cytokines control body temperature and trigger autoimmune disorders in the central nervous system, whereas neuropeptides released in peripheral tissues and lymphoid organs modulate inflammatory (innate) and adaptive immune responses. Surprisingly, the effects of nerve fibers and the antidromic release of its pro-inflammatory neuropeptides on the leukocytes of the immune system that mediate graft rejection are practically unknown. In the transplantation field, such area of research remains practically unexplored. A recent study by Riol-Blanco et al has revealed new details on how nociceptive nerves regulate the pro-inflammatory function of leukocytes in peripheral tissues. Although the mechanism(s) by which neuroinflammation affects the immune response against the allograft remains unknown, recent data suggest that this new area of research is worth exploring for potential development of novel complementary therapies for prevention/treatment of graft rejection.