Acrolein involvement in sensory and behavioral hypersensitivity following spinal cord injury in the rat

Growing evidence suggests that oxidative stress, as associated with spinal cord injury (SCI), may play a critical role in both neuroinflammation and neuropathic pain conditions. The production of the endogenous aldehyde acrolein, following lipid peroxidation during the inflammatory response, may contribute to peripheral sensitization and hyperreflexia following SCI via the TRPA1-dependent mechanism. Here we report that there are enhanced levels of acrolein and increased neuronal sensitivity to the aldehyde for at least 14 days after SCI. Concurrent with injury-induced increases in acrolein concentration is an increased expression of TRPA1 in the lumbar (L3-L6) sensory ganglia. As proof of the potential pronociceptive role for acrolein, intrathecal injections of acrolein revealed enhanced sensitivity to both tactile and thermal stimuli for up to 10 days, supporting the compound’s pro-nociceptive functionality. Treatment of SCI animals with the acrolein scavenger hydralazine produced moderate improvement in tactile responses as well as robust changes in thermal sensitivity for up to 49 days. Taken together, these data suggests that acrolein directly modulates SCI-associated pain behavior, making it a novel therapeutic target for preclinical and clinical SCI as an analgesic

Identification of a functional interaction of HMGB1 with Receptor for Advanced Glycation End-products in a model of neuropathic pain

Recent studies indicate that the release of high mobility group box 1 (HMGB1) following nerve injury may play a central role in the pathogenesis of neuropathic pain. HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs). The degree to which HMGB1 activates a receptor is thought to be dependent upon the oxidative state of the ligand, resulting in the functional isoforms of all-thiol HMGB1 (at-HMGB1) acting through RAGE, and disufide HMGB1 (ds-HMGB1) interacting with TLR4. Though it is known that dorsal root ganglia (DRG) sensory neurons exposed to HMGB1 and TLR4 agonists can influence excitation, the degree to which at-HMGB1 signaling through neuronal RAGE contributes to neuropathic pain is unknown. Here we demonstrate that at-HMGB1 activation of nociceptive neurons is dependent on RAGE and not TLR4. To distinguish the possible role of RAGE on neuropathic pain, we characterized the changes in RAGE mRNA expression up to one month after tibial nerve injury (TNI). RAGE mRNA expression in lumbar dorsal root ganglion (DRG) is substantially increased by post-injury day (PID) 28 when compared with sham injured rodents. Protein expression at PID28 confirms this injury-induced event in the DRG. Moreover, a single exposure to monoclonal antibody to RAGE (RAGE Ab) failed to abrogate pain behavior at PID 7, 14 and 21. However, RAGE Ab administration produced reversal of mechanical hyperalgesia on PID28. Thus, at-HMGB1 activation through RAGE may be responsible for sensory neuron sensitization and mechanical hyperalgesia associated with chronic neuropathic pain states

Climate, people and faunal succession on Java, Indonesia: evidence from Song Gupuh

Song Gupuh, a partially collapsed cave in the Gunung Sewu Limestones of East Java, Indonesia, contains over 16 m of deposits with a faunal sequence spanning some 70 ka. Major changes in the range of animals represented show the impact of climate change and humans. The Terminal Pleistocene and Early Holocene was a period of maximum biodiversity. Human use of Song Gupuh and other cave sites in the region also intensified significantly from ca. 12 ka, together with a new focus on exploitation of small-bodied species (macaque monkeys and molluscs), the first evidence for import of resources from the coast, and use of bone and shell tools. Human activity, especially after the onset of the Neolithic around 2.6 ka, subsequently contributed to a progressive loss of many species from the area, including tapir, elephant, Malayan bear, rhino and tiger, and this extinction process is continuing. We conclude by discussing the biogeographical significance of Song Gupuh in the context of other sites in Java (e.g. Punung, Wajak) and further afield (e.g. Liang Bua)

An integrative geochronological framework for the pleistocene So'a basin (Flores, Indonesia), and its implications for faunal turnover and hominin arrival

Flores represents a unique insular environment with an extensive record of Pleistocene fossil remains and stone artefacts. In the So\u27a Basin of central Flores these include endemic Stegodon, Komodo dragons, giant tortoises, rats, birds and hominins, and lithic artefacts that can be traced back to at least one million years ago (1 Ma). This comprehensive review presents important new data regarding the dating and faunal sequence of the So\u27a Basin, including the site of Mata Menge where Homo floresiensis-like fossils dating to approximately 0.7 Ma were discovered in 2014. By chemical fingerprinting key silicic tephra originating from local and distal eruptive sources we have now established basin-wide tephrostratigraphic correlations, and, together with new numerical ages, present an update of the chronostratigraphy of the So\u27a Basin, with major implications for the faunal sequence. These results show that a giant tortoise and the diminutive proboscidean Stegodon sondaari last occurred at the site of Tangi Talo ∼1.3 Ma, and not 0.9 Ma as previously thought. We also present new data suggesting that the disappearance of giant tortoise and S. sondaari from the sedimentary record occurred before, and/or was coincident with, the earliest hominin arrival, as evidenced by the first records of lithic artefacts occurring directly below the 1 Ma Wolo Sege Tephra. Artefacts become common in the younger layers, associated with a distinct fauna characterized by the medium-sized Stegodon florensis and giant rat Hooijeromys nusatenggara. Furthermore, we describe a newly discovered terrace fill, which extends the faunal record of Stegodon in the So\u27a Basin to the Late Pleistocene. Our evidence also suggests that the paleoenvironment of the So\u27a Basin became drier around the time of the observed faunal transition and arrival of hominins on the island, which could be related to an astronomically-forced climate response at the onset of the Mid-Pleistocene Transition (MPT; ∼1.25 Ma) leading to increased aridity and monsoonal intensity

Identification of the Benzyloxyphenyl Pharmacophore: A Structural Unit That Promotes Sodium Channel Slow Inactivation

Four compounds that contained the N-benzyl 2-amino-3-methoxypropionamide unit were evaluated for their ability to modulate Na+ currents in catecholamine A differentiated CAD neuronal cells. The compounds differed by the absence or presence of either a terminal N-acetyl group or a (3-fluoro)benzyloxy moiety positioned at the 4′-benzylamide site. Analysis of whole-cell patch-clamp electrophysiology data showed that the incorporation of the (3-fluoro)benzyloxy unit, to give the (3-fluoro)benzyloxyphenyl pharmacophore, dramatically enhanced the magnitude of Na+ channel slow inactivation. In addition, N-acetylation markedly increased the stereoselectivity for Na+ channel slow inactivation. Furthermore, we observed that Na+ channel frequency (use)-dependent block was maintained upon inclusion of this pharmacophore. Confirmation of the importance of the (3-fluoro)benzyloxyphenyl pharmacophore was shown by examining compounds where the N-benzyl 2-amino-3-methoxypropionamide unit was replaced by a N-benzyl 2-amino-3-methylpropionamide moiety, as well as examining a series of compounds that did not contain an amino acid group but retained the pharmacophore unit. Collectively, the data indicated that the (3-fluoro)benzyloxyphenyl unit is a novel pharmacophore for the modulation of Na+ currents

Acute respiratory failure in immunocompromised patients : outcome and clinical features according to neutropenia status

Abstract Background The impact of neutropenia in critically ill immunocompromised patients admitted in a context of acute respiratory failure (ARF) remains uncertain. The primary objective was to assess the prognostic impact of neutropenia on outcomes of these patients. Secondary objective was to assess etiology of ARF according to neutropenia. Methods We performed a post hoc analysis of a prospective multicenter multinational study from 23 ICUs belonging to the Nine-I network. Between November 2015 and July 2016, all adult immunocompromised patients with ARF admitted to the ICU were included in the study. Adjusted analyses included: (1) a hierarchical model with center as random effect; (2) propensity score (PS) matched cohort; and (3) adjusted analysis in the matched cohort. Results Overall, 1481 patients were included in this study of which 165 had neutropenia at ICU admission (11%). ARF etiologies distribution was significantly different between neutropenic and non-neutropenic patients, main etiologies being bacterial pneumonia (48% vs 27% in neutropenic and non-neutropenic patients, respectively). Initial oxygenation strategy was standard supplemental oxygen in 755 patients (51%), high-flow nasal oxygen in 165 (11%), non-invasive ventilation in 202 (14%) and invasive mechanical ventilation in 359 (24%). Before adjustment, hospital mortality was significantly higher in neutropenic patients (54% vs 42%; p = 0.006). After adjustment for confounder and center effect, neutropenia was no longer associated with outcome (OR 1.40, 95% CI 0.93–2.11). Similar results were observed after matching (52% vs 46%, respectively; p = 0.35) and after adjustment in the matched cohort (OR 1.04; 95% CI 0.63–1.72). Conclusion Neutropenia at ICU admission is not associated with hospital mortality in this cohort of critically ill immunocompromised patients admitted for ARF. In neutropenic patients, main ARF etiologies are bacterial and fungal infections

Acute respiratory failure in immunocompromised patients:outcome and clinical features according to neutropenia status

Background: The impact of neutropenia in critically ill immunocompromised patients admitted in a context of acute respiratory failure (ARF) remains uncertain. The primary objective was to assess the prognostic impact of neutropenia on outcomes of these patients. Secondary objective was to assess etiology of ARF according to neutropenia. Methods: We performed a post hoc analysis of a prospective multicenter multinational study from 23 ICUs belonging to the Nine-I network. Between November 2015 and July 2016, all adult immunocompromised patients with ARF admitted to the ICU were included in the study. Adjusted analyses included: (1) a hierarchical model with center as random effect; (2) propensity score (PS) matched cohort; and (3) adjusted analysis in the matched cohort. Results: Overall, 1481 patients were included in this study of which 165 had neutropenia at ICU admission (11%). ARF etiologies distribution was significantly different between neutropenic and non-neutropenic patients, main etiologies being bacterial pneumonia (48% vs 27% in neutropenic and non-neutropenic patients, respectively). Initial oxygenation strategy was standard supplemental oxygen in 755 patients (51%), high-flow nasal oxygen in 165 (11%), non-invasive ventilation in 202 (14%) and invasive mechanical ventilation in 359 (24%). Before adjustment, hospital mortality was significantly higher in neutropenic patients (54% vs 42%; p = 0.006). After adjustment for confounder and center effect, neutropenia was no longer associated with outcome (OR 1.40, 95% CI 0.93–2.11). Similar results were observed after matching (52% vs 46%, respectively; p = 0.35) and after adjustment in the matched cohort (OR 1.04; 95% CI 0.63–1.72). Conclusion: Neutropenia at ICU admission is not associated with hospital mortality in this cohort of critically ill immunocompromised patients admitted for ARF. In neutropenic patients, main ARF etiologies are bacterial and fungal infections.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Assets and domestic units: methodological challenges for longitudinal studies of poverty dynamics

Tracking change in assets access and ownership in longitudinal research is difficult. Assets are rarely assigned to individuals. Their benefit and management are spread across domestic units which morph over time. We review the challenges of using assets to understand poverty dynamics, and tracking the domestic units that own and manage assets. Using case studies from longitudinal research we demonstrate that assets can afford useful insights into important change