Early detection of the initial stages of LED light-triggered non-alcoholic fatty liver disease by wax physisorption kinetics-Fourier transform infrared imaging.

Light-emitting diodes (LEDs), particularly in the blue waveform range, are regarded as a major source of circadian rhythm dysregulation. A circadian rhythm dysregulation induced by blue LEDs is associated with non-alcoholic fatty liver disease (NAFLD). Hepatocellular accumulation of lipids is a key event in the early stages of NAFLD. Kupffer cells (KCs) have been reported to be lost in the early onset of NAFLD followed by an inflammatory reaction that alters the liver response to lipid overload. This study focused on the detection of the initial stages (subpathological stages) of LED light-triggered NAFLD. Mice were exposed to either blue or white LED irradiation for 44 weeks. Synchrotron radiation-based Fourier-transform infrared microspectroscopy (SR-FTIRM) and wax physisorption kinetic-Fourier transform infrared (WPK-FTIR) imaging were used to evaluate the ratio of lipid to protein and the glycosylation of glycoprotein, respectively. Immunohistopathological studies on KCs and circadian-related proteins were performed. Although liver biopsy showed normal pathology, an SR-FTIRM study revealed a high hepatic lipid-to-protein ratio after receiving LED illumination. The results of WPK-FTIR demonstrated that a high inflammation index was found in the high irradiance of the blue LED illumnation group. These groups showed a decrease in KC number and an increase in Bmal1 and Reverbα circadian protein expression. These findings provide explanations for the reduction of KCs without subsequent inflammation. A significant reduction of Per2 and Cry1 expression is correlated with the findings of WPK-FTIR imaging. WPK-FTIR is a sensitive method for detecting initiative stages of NAFLD induced by long-term blue LED illumination.

SEPT9 Upregulation in Satellite Glial Cells Associated with Diabetic Polyneuropathy in a Type 2 Diabetes-like Rat Model.

Despite the worldwide prevalence and severe complications of type 2 diabetes mellitus (T2DM), the pathophysiological mechanisms underlying the development of diabetic polyneuropathy (DPN) are poorly understood. Beyond strict control of glucose levels, clinical trials for reversing DPN have largely failed. Therefore, understanding the pathophysiological and molecular mechanisms underlying DPN is crucial. Accordingly, this study explored biochemical and neuropathological deficits in a rat model of T2DM induced through high-fat diet (HFD) feeding along with two low-dose streptozotocin (STZ) injections; the deficits were explored through serum lipid, neurobehavioral, neurophysiology, neuropathology, and immunohistochemistry examinations. Our HFD/STZ protocol induced (1) mechanical hyperalgesia and depression-like behaviors, (2) loss of intraepidermal nerve fibers (IENFs) and reduced axonal diameters in sural nerves, and (3) decreased compound muscle action potential. In addition to hyperglycemia, which was correlated with the degree of mechanical hyperalgesia and loss of IENFs, we observed that hypertriglyceridemia was the most dominant deficit in the lipid profiles of the diabetic rats. In particular, SEPT9, the fourth component of the cytoskeleton, increased in the satellite glial cells (SGCs) of the dorsal root ganglia (DRG) in the T2DM-like rats. The number of SEPT9(+) SGCs/DRG was correlated with serum glucose levels and mechanical thresholds. Our findings indicate the putative molecular mechanism underlying DPN, which presumably involves the interaction of SGCs and DRG neurons; nevertheless, further functional research is warranted to clarify the role of SEPT9 in DPN.

Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy.

We investigated the mediating roles of activating transcription factor 3 (ATF3), an injury marker, or C-type lectin member 5A (CLEC5A), an inflammatory response molecule, in the induction of endoplasmic reticulum (ER) stress and neuroinflammation in diabetic peripheral neuropathy in ATF3 and CLEC5A genetic knockout (aft3-/- and clec5a-/-, respectively) mice. ATF3 was expressed intranuclearly and was upregulated in mice with diabetic peripheral neuropathy (DN) and clec5a-/- mice. The DN and clec5a-/- groups also exhibited neuropathic behavior, but not in the aft3-/- group. The upregulation profiles of cytoplasmic polyadenylation element-binding protein, a protein translation-regulating molecule, and the ER stress-related molecules of inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α in the DN and clec5a-/- groups were correlated with neuropathic behavior. Ultrastructural evidence confirmed ER stress induction and neuroinflammation, including microglial enlargement and proinflammatory cytokine release, in the DN and clec5a-/- mice. By contrast, the induction of ER stress and neuroinflammation did not occur in the aft3-/- mice. Furthermore, the mRNA of reactive oxygen species-removing enzymes such as superoxide dismutase, heme oxygenase-1, and catalase were downregulated in the DN and clec5a-/- groups but were not changed in the aft3-/- group. Taken together, the results indicate that intraneuronal ATF3, but not CLEC5A, mediates the induction of ER stress and neuroinflammation associated with diabetic neuropathy.

Onsite telemedicine strategy for coronavirus (COVID-19) screening to limit exposure in ED.

Coronavirus (severe acute respiratory syndrome coronavirus 2) outbreak is a public health emergency and a global pandemic. During the present coronavirus disease (COVID-19) crisis, telemedicine has been recommended to screen suspected patients to limit risk of exposure and maximise medical staff protection. We constructed the protective physical barrier with telemedicine technology to limit COVID-19 exposure in ED. Our hospital is an urban community hospital with annual ED volume of approximately 50 000 patients. We equipped our patient exam room with intercom and iPad for telecommunication. Based on our telemedicine screening protocol, physician can conduct a visual physical examination on stable patients via intercom or videoconference. Telemedicine was initially used to overcome the physical barrier between patients and physicians. However, our protocol is designed to create a protective physical barrier to protect healthcare workers and enhance efficiency in ED. The implementation can be a promising protocol in making ED care more cost-effective and efficient during the COVID-19 pandemic and beyond.

EXPRESS: NGF-trkA signaling modulates the analgesic effects of prostatic acid phosphatase in resiniferatoxin-induced neuropathy.

BACKGROUND: Neuropathic pain in small-fiber neuropathy results from injury to and sensitization of nociceptors. Functional prostatic acid phosphatase (PAP) acts as an analgesic effector. However, the mechanism responsible for the modulation of PAP neuropathology, which leads to loss of the analgesic effect after small-fiber neuropathy, remains unclear. RESULTS: We used a resiniferatoxin (RTX)-induced small-fiber neuropathy model to examine whether functional PAP(þ) neurons are essential to maintain the analgesic effect. PAP(þ) neurons were categorized into small to medium neurons (25th-75th percentile: 17.1-23.7 mm); these neurons were slightly reduced by RTX (p»0.0003). By contrast, RTX-induced activating transcription factor 3 (ATF3), an injury marker, in PAP(þ) neurons (29.0%5.6% vs. 0.2%0.2%, p»0.0043), indicating PAP neuropathology. Moreover, the high-affinity nerve growth factor (NGF) receptor (trkA) colocalized with PAP and showed similar profiles after RTX-induced neuropathy, and the PAP/trkA ratios correlated with the degree of mechanical allodynia (r»0.62, p»0.0062). The NGF inducer 4-methylcatechol (4MC) normalized the analgesic effects of PAP; specifically, it reversed the PAP and trkA profiles and relieved mechanical allodynia. Administering 2.5S NGF showed similar results to those of administering 4MC. This finding suggests that the analgesic effect of functional PAP is mediated by NGF-trkA signaling, which was confirmed by NGF neutralization. CONCLUSIONS: This study revealed that functional PAP(þ) neurons are essential for the analgesic effect, which is mediated by NGF-trkA signaling.

Mitochondrial fission augments capsaicin-induced axonal degeneration.

Capsaicin, an agonist of transient receptor potential vanilloid receptor 1, induces axonal degeneration of peripheral sensory nerves and is commonly used to treat painful sensory neuropathies. In this study, we investigated the role of mitochondrial dynamics in capsaicin-induced axonal degeneration. In capsaicin-treated rodent sensory axons, axonal swellings, decreased mitochondrial stationary site length and reduced mitochondrial transport preceded axonal degeneration. Increased axoplasmic Ca(2+) mediated the alterations in mitochondrial length and transport. While sustaining mitochondrial transport did not reduce axonal swellings in capsaicin-treated axons, preventing mitochondrial fission by overexpression of mutant dynamin-related protein 1 increased mitochondrial length, retained mitochondrial membrane potentials and reduced axonal loss upon capsaicin treatment. These results establish that mitochondrial stationary site size significantly affects axonal integrity and suggest that inhibition of Ca(2+)-dependent mitochondrial fission facilitates mitochondrial function and axonal survival following activation of axonal cationic channels.

Determinants of nerve conduction recovery after nerve injuries: Compression duration and nerve fiber types.

INTRODUCTION: The aims of this study were to determine the influences of: (1) timing of nerve decompression; and (2) nerve fiber types on the patterns of nerve conduction studies (NCS) after nerve injury. METHODS: Nerve conduction studies (NCS) were performed on 3 models of nerve injury: (1) crush injury due to transient nerve compression (crush group); (2) chronic constriction injury (CCI), or permanent compression (CCI group); and (3) CCI with removal of ligatures, or delayed nerve decompression (De-CCI group). RESULTS: There were distinct patterns of NCS recovery. The crush and De-CCI groups achieved similar motor nerve recovery, better than that of the CCI group. In contrast, recovery of sensory nerves was limited in the CCI and De-CCI groups and was lower than in the crush group. CONCLUSIONS: Immediate relief of compression resulted in the best recovery of motor and sensory nerve conduction. In contrast, delayed decompression restored only motor nerve conduction.

Effects of Antrodia camphorata extracts on anti-oxidation, anti-mutagenesis and protection of DNA against hydroxyl radical damage.

BACKGROUND: Antrodia camphorata is a geographically special fungus and is one of the precious traditional medicines of Taiwan. A lot of reports have addressed its antioxidant activities and anticancer activities. In order to understand whether these protection effects were resulted from its ability of preventing DNA against hydroxyl radical damage, the A. camphorata extract was used to examine its antioxidant, antimutagenic and DNA-protective activities. METHODS: A. camphorata extract was prepared by extracting the lyophilized powder of A. camphorata mycelium with distilled water. The antioxidative activity of this A. camphorata extract was then evaluated by 2,2-diphenyl-1-picrylhydrozyl (DPPH) radical-scavenging assay, and the antimutagenic activities of the extract against direct mutagen 4-nitroquinoline N-oxide (4NQNO) and indirect mutagen benzo[a]pyrene (B[a]P) were evaluated by Ames test. The effects of the A. camphorata extract in terms of DNA protection against hydroxyl radical damage were also investigated. RESULTS: It was found that the higher the concentration of A. camphorata extracts, the higher the DPPH radical-scavenging effect. A. camphorata extract at concentrations between 0.625 and 10 mg/ml was found to be neither toxic nor mutagenic. However, the higher A. camphorata concentration (10 mg/ml) used in the test showed higher inhibitory effects on 4NQNO in a dose-dependent manner. The A. camphorata extract also showed reducing and scavenging activities against superoxide anion radical and also exhibited protective effects on DNA against hydroxyl radical-induced damage. CONCLUSIONS: Results suggested that A. camphorata is a non-toxic and novel material with antioxidant, antimutagenic and DNA-protective activities and could be developed into health foods.

Nerve demyelination increases metabotropic glutamate receptor subtype 5 expression in peripheral painful mononeuropathy.

Wallerian degeneration or nerve demyelination, arising from spinal nerve compression, is thought to bring on chronic neuropathic pain. The widely distributed metabotropic glutamate receptor subtype 5 (mGluR5) is involved in modulating nociceptive transmission. The purpose of this study was to investigate the potential effects of mGluR5 on peripheral hypersensitivities after chronic constriction injury (CCI). Sprague-Dawley rats were operated on with four loose ligatures around the sciatic nerve to induce thermal hyperalgesia and mechanical allodynia. Primary afferents in dermis after CCI exhibited progressive decreases, defined as partial cutaneous denervation; importantly, mGluR5 expressions in primary afferents were statistically increased. CCI-induced neuropathic pain behaviors through the intraplantar injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective mGluR5 antagonist, were dose-dependently attenuated. Furthermore, the most increased mGluR5 expressions in primary afferents surrounded by reactive Schwann cells were observed at the distal CCI stumps of sciatic nerves. In conclusion, these results suggest that nerve demyelination results in the increases of mGluR5 expression in injured primary afferents after CCI; and further suggest that mGluR5 represents a main therapeutic target in developing pharmacological strategies to prevent peripheral hypersensitivities.

Enhancement of purinergic signalling by excessive endogenous ATP in resiniferatoxin (RTX) neuropathy.

ATP is a ligand of P2X family purinoceptors, and exogenous ATP administration evokes pain behaviors. To date, there is a lack of systematic studies to address relationships between endogenous ATP and neuropathic pain. In this report, we took advantage of a mouse model of resiniferatoxin (RTX)-induced neuropathic pain to address the role of endogenous ATP in neuropathic pain. After RTX administration, endogenous ATP markedly increased in dorsal root ganglia (DRGs) (p < 0.01) and skin tissues (p < 0.001). The excessive endogenous ATP was removed by apyrase, an ATP hydrolyzing enzyme, administration via either a lumbar puncture route (p < 0.001) or an intraplantar injection (p < 0.001), which led to the normalization of neuropathic pain. In addition, intraplantar treatment with apyrase caused mechanical analgesia. Linear analyses showed that the densities of P2X3(+) neurons (r = -0.72, p < 0.0001) and P2X3(+) dermal nerves (r = -0.72, p < 0.0001) were inversely correlated with mechanical thresholds. Moreover, the contents of endogenous ATP in skin tissues were linearly correlated with P2X3(+) dermal nerves (r = 0.80, p < 0.0001) and mechanical thresholds (r = -0.80, p < 0.0001). In summary, this study demonstrated that enhanced purinergic signalling due to an increase in endogenous ATP after RTX-induced nerve injury contributed to the development of neuropathic pain. The data in this report provide a new therapeutic strategy for pain control by targeting the endogenous ligand of purinergic signalling.

Roles of Neuronal Protein Kinase Cε on Endoplasmic Reticulum Stress and Autophagic Formation in Diabetic Neuropathy.

In chronic diabetic neuropathy (DN), the cellular mechanisms of neuropathic pain remain unclear. Protein kinase C epsilon (PKCε) is an intracellular signaling molecule that mediates chronic pain. This paper addresses the long-term upregulated PKCε in DN associated with endoplasmic reticulum (ER) stress and autophagic formation and correlates to chronic neuropathic pain. We found that thermal hyperalgesia and mechanical allodynia course development were associated with PKCε upregulation after DN but not skin denervation. Pathologically, PKCε upregulation was associated with the expression of inositol-requiring enzyme 1α (IRE1α; ER stress-related molecule) and ubiquitin D (UBD), which are involved in the ubiquitin-proteasome system (UPS)-mediated degradation of misfolded proteins under ER stress. Manders coefficient analyses revealed an approximately 50% colocalized ratio for IRE1α(+):PKCε(+) neurons (0.34-0.48 for M1 and 0.40-0.58 for M2 Manders coefficients). The colocalized coefficients of UBD/PKCε increased (M1: 0.33 ± 0.03 vs. 0.77 ± 0.04, p < 0.001; M2: 0.29 ± 0.05 vs. 0.78 ± 0.04; p < 0.001) in the acute DN stage. In addition, the regulatory subunit p85 of phosphoinositide 3-kinase, which is involved in regulating insulin signaling, exhibited similar expression patterns to those of IRE1α and UBD; for example, it had highly colocalized ratios to PKCε. The ultrastructural examination further confirmed that autophagic formation was associated with PKCε upregulation. Furthermore, PKCεv1-2, a PKCε specific inhibitor, reverses neuropathic pain, ER stress, and autophagic formation in DN. This finding suggests PKCε plays an upstream molecule in DN-associated neuropathic pain and neuropathology and could provide a potential therapeutic target.

Transient receptor potential vanilloid subtype 1 depletion mediates mechanical allodynia through cellular signal alterations in small-fiber neuropathy.

Transient receptor potential vanilloid subtype 1 (TRPV1) is a polymodal nociceptor that monitors noxious thermal sensations. Few studies have addressed the role of TRPV1 in mechanical allodynia in small-fiber neuropathy (SFN) caused by sensory nerve damage. Accordingly, this article reviews the putative mechanisms of TRPV1 depletion that mediates mechanical allodynia in SFN. The intraepidermal nerve fibers (IENFs) degeneration and sensory neuronal injury are the primary characteristics of SFN. Intraepidermal nerve fibers are mainly C-polymodal nociceptors and Aδ-fibers, which mediated allodynic pain after neuronal sensitization. TRPV1 depletion by highly potent neurotoxins induces the upregulation of activating transcription factor 3 and IENFs degeneration which mimics SFN. TRPV1 is predominately expressed by the peptidergic than nonpeptidergic nociceptors, and these neurochemical discrepancies provided the basis of the distinct pathways of thermal analgesia and mechanical allodynia. The depletion of peptidergic nociceptors and their IENFs cause thermal analgesia and sensitized nonpeptidergic nociceptors respond to mechanical allodynia. These distinct pathways of noxious stimuli suggested determined by the neurochemical-dependent neurotrophin cognate receptors such as TrkA and Ret receptors. The neurogenic inflammation after TRPV1 depletion also sensitized Ret receptors which results in mechanical allodynia. The activation of spinal TRPV1(+) neurons may contribute to mechanical allodynia. Also, an imbalance in adenosinergic analgesic signaling in sensory neurons such as the downregulation of prostatic acid phosphatase and adenosine A1 receptors, which colocalized with TRPV1 as a membrane microdomain also correlated with the development of mechanical allodynia. Collectively, TRPV1 depletion-induced mechanical allodynia involves a complicated cascade of cellular signaling alterations.

Clinical Features of Emergency Department Patients from Early COVID-19 Pandemic that Predict SARS-CoV-2 Infection: Machine-learning Approach.

INTRODUCTION: Within a few months coronavirus disease 2019 (COVID-19) evolved into a pandemic causing millions of cases worldwide, but it remains challenging to diagnose the disease in a timely fashion in the emergency department (ED). In this study we aimed to construct machine-learning (ML) models to predict severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection based on the clinical features of patients visiting an ED during the early COVID-19 pandemic. METHODS: We retrospectively collected the data of all patients who received reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 at the ED of Baylor Scott & White All Saints Medical Center, Fort Worth, from February 23-May 12, 2020. The variables collected included patient demographics, ED triage data, clinical symptoms, and past medical history. The primary outcome was the confirmed diagnosis of COVID-19 (or SARS-CoV-2 infection) by a positive RT-PCR test result for SARS-CoV-2, and was used as the label for ML tasks. We used univariate analyses for feature selection, and variables with P<0.1 were selected for model construction. Samples were split into training and testing cohorts on a 60:40 ratio chronologically. We tried various ML algorithms to construct the best predictive model, and we evaluated performances with the area under the receiver operating characteristic curve (AUC) in the testing cohort. RESULTS: A total of 580 ED patients were tested for SARS-CoV-2 during the study periods, and 98 (16.9%) were identified as having the SARS-CoV-2 infection based on the RT-PCR results. Univariate analyses selected 21 features for model construction. We assessed three ML methods for performance: of the three methods, random forest outperformed the others with the best AUC result (0.86), followed by gradient boosting (0.83) and extra trees classifier (0.82). CONCLUSION: This study shows that it is feasible to use ML models as an initial screening tool for identifying patients with SARS-CoV-2 infection. Further validation will be necessary to determine how effectively this prediction model can be used prospectively in clinical practice.

Intraosseous versus intravenous vascular access during cardiopulmonary resuscitation for out-of-hospital cardiac arrest: a systematic review and meta-analysis of observational studies.

INTRODUCTION: This study is aimed to investigate the association of intraosseous (IO) versus intravenous (IV) route during cardiopulmonary resuscitation (CPR) with outcomes after out-of-hospital cardiac arrest (OHCA). METHODS: We systematically searched PubMed, Embase, Cochrane Library and Web of Science from the database inception through April 2020. Our search strings included designed keywords for two concepts, i.e. vascular access and cardiac arrest. There were no limitations implemented in the search strategy. We selected studies comparing IO versus IV access in neurological or survival outcomes after OHCA. Favourable neurological outcome at hospital discharge was pre-specified as the primary outcome. We pooled the effect estimates in random-effects models and quantified the heterogeneity by the I2 statistics. Time to intervention, defined as time interval from call for emergency medical services to establishing vascular access or administering medications, was hypothesized to be a potential outcome moderator and examined in subgroup analysis with meta-regression. RESULTS: Nine retrospective observational studies involving 111,746 adult OHCA patients were included. Most studies were rated as high quality according to Newcastle-Ottawa Scale. The pooled results demonstrated no significant association between types of vascular access and the primary outcome (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.27-1.33; I2, 95%). In subgroup analysis, time to intervention was noted to be positively associated with the pooled OR of achieving the primary outcome (OR: 3.95, 95% CI, 1.42-11.02, p: 0.02). That is, when the studies not accounting for the variable of "time to intervention" in the statistical analysis were pooled together, the meta-analytic results between IO access and favourable outcomes would be biased toward inverse association. No obvious publication bias was detected by the funnel plot. CONCLUSIONS: The meta-analysis revealed no significant association between types of vascular access and neurological outcomes at hospital discharge among OHCA patients. Time to intervention was identified to be an important outcome moderator in this meta-analysis of observation studies. These results call for the need for future clinical trials to investigate the unbiased effect of IO use on OHCA CPR.

Early versus Late Surgical Decompression for Traumatic Spinal Cord Injury on Neurological Recovery: A Systematic Review and Meta-Analysis.

This study aimed to investigate whether early surgical decompression was associated with favorable neurological recovery in patients with traumatic spinal cord injury (tSCI). We searched PubMed and Embase from the database inception through December 2020 and selected studies comparing the impact of early versus late surgical decompression on neurological recovery as assessed by American Spinal Injury Association Impairment Scale (AIS) for adult patients sustaining tSCI. We pooled the effect estimates in random-effects models and quantified the heterogeneity by the I2 statistics. Subgroup analysis and meta-regression analysis was conducted to identify significant outcome moderator. We included 26 studies involving 3574 patients in the meta-analysis. The pooled results demonstrated significant association between early surgical decompression and an improvement of at least one AIS grade (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.41-2.41; I2, 48.06%). The benefits of early surgical decompression were consistently observed across different subgroups, including patients with cervical or thoracolumbar injury and patients with complete or incomplete injury. The meta-regression analysis indicated that cut-off timing defining early versus late decompression was a significant effect moderator, with early decompression performed before post-tSCI 8 or 12 h associated with greatest benefits (OR, 3.37; 95% CI, 1.74-6.50; I2, 53.52%). No obvious publication bias was detected by the funnel plot. In conclusion, early surgical decompression was associated with favorable neurological recovery for tSCI patients. However, there was a lack of high-quality evidence and the results need further examination.

A retrospective study on the therapeutic effects of sodium bicarbonate for adult in-hospital cardiac arrest.

To investigate whether the effects of sodium bicarbonate (SB) during cardiopulmonary resuscitation (CPR) would be influenced by blood pH and administration timing. Adult patients experiencing in-hospital cardiac arrest (IHCA) from 2006 to 2015 were retrospectively screened. Early intra-arrest blood gas data were obtained within 10 min of CPR. Multivariable logistic regression analysis and generalised additive models were used for effect estimation and data exploration, respectively. A total of 1060 patients were included. Only 59 patients demonstrated favourable neurological status at hospital discharge. Blood pH ≤ 7.18 was inversely associated with favourable neurological outcome (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11-0.52; p value < 0.001) while SB use was not. In the interaction analysis for favourable neurological outcome, significant interactions were noted between SB use and time to SB (SB use × time to SB ≥ 20 min; OR 6.16; 95% CI 1.42-26.75; p value = 0.02). In the interaction analysis for survival to hospital discharge, significant interactions were noted between SB use and blood pH (Non-SB use × blood pH > 7.18; OR 1.56; 95% CI 1.01-2.41; p value = 0.05). SB should not be empirically administered for patients with IHCA since its effects may be influenced by blood pH and administration timing.

Peripheral Neuropathic Pain: From Experimental Models to Potential Therapeutic Targets in Dorsal Root Ganglion Neurons.

Neuropathic pain exerts a global burden caused by the lesions in the somatosensory nerve system, including the central and peripheral nervous systems. The mechanisms of nerve injury-induced neuropathic pain involve multiple mechanisms, various signaling pathways, and molecules. Currently, poor efficacy is the major limitation of medications for treating neuropathic pain. Thus, understanding the detailed molecular mechanisms should shed light on the development of new therapeutic strategies for neuropathic pain. Several well-established in vivo pain models were used to investigate the detail mechanisms of peripheral neuropathic pain. Molecular mediators of pain are regulated differentially in various forms of neuropathic pain models; these regulators include purinergic receptors, transient receptor potential receptor channels, and voltage-gated sodium and calcium channels. Meanwhile, post-translational modification and transcriptional regulation are also altered in these pain models and have been reported to mediate several pain related molecules. In this review, we focus on molecular mechanisms and mediators of neuropathic pain with their corresponding transcriptional regulation and post-translational modification underlying peripheral sensitization in the dorsal root ganglia. Taken together, these molecular mediators and their modification and regulations provide excellent targets for neuropathic pain treatment.

Association of ultrasound-related interruption during cardiopulmonary resuscitation with adult cardiac arrest outcomes: A video-reviewed retrospective study.

OBJECTIVES: To determine the association of focused transthoracic echocardiography (ECHO) related interruption during cardiopulmonary resuscitation (CPR) with patient outcomes in the Emergency Department (ED). METHODS: This was a retrospective, single center, cohort study, conducted in an urban community teaching ED. Eligible study subjects were adult patients in the ED with sustained cardiac arrest. Exclusion criteria include traumatic cardiac arrest and age less than 18. All resuscitations were video recorded and were subsequently reviewed by 2 study investigators. The no-flow time from chest compression interruption was analyzed using video review and separated into ECHO-related and non-ECHO related. Our primary outcome was patient survival to hospital discharge and the secondary outcome was the rate of return of spontaneous circulation (ROSC). Multivariate logistic regression analyses were performed to examine the associations between independent variables and outcomes. RESULTS: From January 2016 to May 2017, a total of 210 patients were included for final analysis. The median total no-flow time observed on video was 99.5 s (IQR: 54.0-160.0 s). Among these, a median of 26.5 s (IQR: 0.0-59.0 s) was ECHO-related and a median of 60.5 s (IQR: 34.0-101.9) was non-ECHO-related. The ECHO-related no-flow time between 77 and 122 s (OR: 7.31, 95 % confidence interval [CI]: 1.59-33.59; p-value = 0.01) and ECHO-related interruption ≦ 2 times (OR: 8.22, 95% CI: 1.51-44.64; p-value = 0.01) were positively associated with survival to hospital discharge. ECHO-related interruption ≦ 2 times (OR: 5.55, 95% CI: 2.44-12.61; p-value < 0.001) was also positively associated with ROSC. CONCLUSION: Short ECHO-related interruption during CPR was positively associated with ROSC and survival to hospital discharge. While ECHO can be a valuable diagnostic tool during CPR, the no-flow time associated with ECHO should be minimized.

Activating transcription factor 3 modulates protein kinase C epsilon activation in diabetic peripheral neuropathy.

BACKGROUND: Skin denervation that develops in patients with diabetes mellitus as a neuropathic manifestation is known as diabetic peripheral neuropathy (DPN). Skin denervation is parallel to neuronal injuries that alter intracellular signaling. To date, the correlation between nerve injury and the activation of intracellular responses to neuropathic manifestations has not been elucidated; specifically, whether activating transcription factor 3 (ATF3) is responsible for neuronal injury and a critical molecule that modulates the activation of intracellular protein kinase C epsilon (p-PKCε) and pain development in DPN is a crucial question. METHODS: To address, ATF3 knockout (atf3 -/- group, C57/B6 genetic background) and wild-type mice (atf3+/+ group) received a single dose of streptozotocin (200 mg/kg) to generate a mouse model of DPN. RESULTS: Both atf3+/+ and atf3 -/- mice exhibited hyperglycemia and the same pathology of skin denervation at posttreatment month 2, but only atf3+/+ mice developed thermal hyperalgesia (P<0.001) and mechanical allodynia (P=0.002). The atf3+/+ group, but not the atf3 -/- group, had preferential ATF3 upregulation on p-PKCε(+) neurons with a ratio of 37.7%±6.1% in p-PKCε(+):ATF3(+) neurons (P<0.001). In addition, B-cell lymphoma-extra large (Bcl-XL), an antiapoptotic Bcl2 family protein, exhibited parallel patterns to p-PKCε (ie, Bcl-XL upregulation was reversed in atf3 -/- mice). These two molecules were colocalized and increased by approximately two-fold in the atf3+/+ group compared with the atf3 -/- group (30.0%±3.4% vs 13.7% ± 6.2%, P=0.003). Furthermore, linear analysis results showed that the densities of p-PKCε and Bcl-XL had a reverse linear relationship with the degrees of thermal hyperalgesia and mechanical allodynia. CONCLUSION: Collectively, this report suggested that ATF3 is a critical upstream molecule that modulates p-PKCε and Bcl-XL expression, which consequently mediated the development of neuropathic manifestation in DPN.