Machine learning-based model for predicting major adverse cardiovascular and cerebrovascular events in patients aged 65 years and older undergoing noncardiac surgery.

BACKGROUND: Few evidence-based prediction models have been developed for predicting major adverse cardiovascular and cerebrovascular events (MACCE) in patients aged 65 years or older undergoing noncardiac surgery. In this study, we aimed to analyze the risk factors for perioperative MACCE in patients aged 65 years or older undergoing noncardiac surgery and construct a prediction model. METHODS: In this nested case-control study, a total of 342 Chinese patients who were aged ≥ 65 years and underwent medium- or high-risk noncardiac surgery in our hospital were included. There were 84 cases with MACCE (the MACCE group) and 258 without MACCE (the control group). Univariable logistic regression analysis was performed to identify the risk factors for MACCE. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the variables. Nomogram was constructed using the selected variables. Machine learning methods, including Decision Tree, XGBoost, Support Vector Machine, K-nearest Neighbor, and Neural network, was used to establish, validate, and compare the performance of different prediction models. RESULTS: A prediction model based on nine variables, including age ≥ 85 years, history of ischemic chest pain, symptoms of decompensated heart failure, high-risk surgery, intraoperative minimum systolic blood pressure, postoperative systolic blood pressure, Cr levels over 2.0 mg/dL, left ventricular ejection fraction, and perioperative blood transfusion, was constructed. This LASSO logistic regression model showed good discriminatory ability to predict MACCE (area under the curve = 0.89; 95% confidence interval, 0.818 - 0.963) and fit to the test set (Hosmer-Lemeshow, χ2 = 7.4053, P = 0.4936). The decision curve analysis showed a positive net benefit of the new model. Compared with logistic regression model, the XGBoost model showed better prediction ability (area under the curve = 0.903). A preoperative prediction model based on five variables, including age ≥ 85 years, symptoms of decompensated heart failure, ischemic chest pain, high-risk type of surgery and Cr levels over 2.0 mg/dL was also constructed. This model showed good discriminatory ability to predict MACCE before surgery (area under the curve = 0.720 [95% CI, 0.591-0.848]. Both models compared with the modified RCRI score had improvement in reclassification. CONCLUSION: By analyzing Chinese patients aged ≥ 65 years undergoing medium- or high-risk noncardiac surgery, the risk factors for perioperative MACCE were identified. Then, simple prediction models were constructed and validated, which showed good prediction performance and may be used as a decision-making assistant tool for clinicians. These findings provide a basis for preventing and improving the perioperative management of MACCE.

Ghrelin signalling in AgRP neurons links metabolic state to the sensory regulation of AgRP neural activity.

OBJECTIVE: The sensory detection of food and food cues suppresses Agouti related peptide (AgRP) neuronal activity prior to consumption with greatest suppression occurring in response to highly caloric food or interoceptive energy need. However, the interoceptive mechanisms priming an appropriate AgRP neural response to external sensory information of food availability remain unexplored. Since hunger increases plasma ghrelin, we hypothesized that ghrelin receptor (GHSR) signalling on AgRP neurons is a key interoceptive mechanism integrating energy need with external sensory cues predicting caloric availability. METHODS: We used in vivo photometry to measure the effects of ghrelin administration or fasting on AgRP neural activity with GCaMP6s and dopamine release in the nucleus accumbens with GRAB-DA in mice lacking ghrelin receptors in AgRP neurons. RESULTS: The deletion of GHSR on AgRP neurons prevented ghrelin-induced food intake, motivation and AgRP activity. The presentation of food (peanut butter pellet) or a wooden dowel suppressed AgRP activity in fasted WT but not mice lacking GHSRs in AgRP neurons. Similarly, peanut butter and a wooden dowel increased dopamine release in the nucleus accumbens after ip ghrelin injection in WT but not mice lacking GHSRs in AgRP neurons. No difference in dopamine release was observed in fasted mice. Finally, ip ghrelin administration did not directly increase dopamine neural activity in the ventral tegmental area. CONCLUSIONS: Our results suggest that AgRP GHSRs integrate an interoceptive state of energy need with external sensory information to produce an optimal change in AgRP neural activity. Thus, ghrelin signalling on AgRP neurons is more than just a feedback signal to increase AgRP activity during hunger.

Exogenous melatonin mitigates saline-alkali stress by decreasing DNA oxidative damage and enhancing photosynthetic carbon metabolism in soybean (Glycine max [L.] Merr.) leaves.

Saline-alkali stress (SS) is a common abiotic stress affecting crop cultivation worldwide, seriously inhibiting plant growth and biomass accumulation. Melatonin has been proven to relieve the inhibition of multiple abiotic stresses on plant growth. Therefore, soybean cultivars Heihe 49 (HH49, SS-tolerant) and Henong 95 (HN95, SS-sensitive) were pot-cultured in SS soil and then treated with 300 µM melatonin at the V1 stage, when the first trifoliate leaves were fully unfolded, to investigate if melatonin has an effect on SS. SS increased reactive oxygen species (ROS) accumulation in soybean leaves and thereby induced DNA oxidative damage. In addition, SS retarded cell growth and decreased the mesophyll cell size, chloroplast number, photosynthetic pigment content, which further reduced the light energy capture and electron transport rate in soybean leaves, and affected carbohydrate accumulation and metabolism. However, melatonin treatment reduced SS-induced ROS accumulation in the soybean leaves by increasing antioxidant content and oxidase activity. Effective removal of ROS reduced SS-induced DNA oxidative damage in the soybean leaf genome, which was represented by decreased random-amplified polymorphic DNA polymorphism, 8-hydroxy-20-deoxyguanine content, and relative density of apurinic/apyrimidinic-sites. Melatonin treatment also increased the volume of mesophyll cells, the numbers of chloroplast and starch grains, the contents of chlorophyll a and b and carotenoids in soybean seedling leaves treated with SS, thereby increasing the efficiency of effective light capture and electron transfer and improving photosynthesis. Subsequently, carbohydrate accumulation and metabolism in soybean leaves under SS were improved by melatonin treatment, which contributes to providing basic substances and energy for cell growth and metabolism, ultimately improving soybean SS tolerance.

Efficient nitrogen removal from mature landfill leachate by single-stage partial-nitritation anammox using expanded granular sludge bed.

The effective retention of anaerobic ammonia oxidizing (anammox) bacteria and its high sensitivity to toxic substances and oxygen posed a major challenge to the application of partial nitrification combined with anammox (PN/A) in mature landfill leachate treatment, although it is a promising and efficient nitrogen removal process. In this study, a single-stage PN/A process based on expanded granular sludge bed was proposed to treat the mature landfill leachate. During the last phase, when the NH+ 4-N concentration of mature landfill leachate in influent was 1150.0 mg/L, the nitrogen removal efficiency (NRE) was 83.64% with 1.07 kg N/(m3·d) nitrogen removal rate (NRR). The activity of anammox bacteria (AnAOB) and ammonia oxidizing bacteria (AOB) was 9.21 ± 0.22 mg N/(gVSS·h) and 14.34 ± 0.65 mg N/(gVSS·h), respectively. The bacteria produced a high amount of tightly bound extracellular polymeric substance (TB-EPS) i.e., 4071.79 mg/(g·VSS). This helped to create granular sludge and provided favorable spatial conditions for the distribution of functional bacteria that were adapted to different environments. Due to the efficient retention of functional bacteria by the granular sludge, the relative abundance of Ca.Brocadia and Ca.Kuneneia was 1.71% and 0.31%, respectively. Redundancy analysis (RDA) and microbial correlation network diagram showed that the relative abundance of Ca. Kuenenia, Nitrosomonas and Truepera had a stronger positive correlation with the increase of the proportion of mature landfill leachate added to the influent. Overall, the PN/A process based on granular sludge provides an effective method for autotrophic biological nitrogen removal from mature landfill leachate.

Optofluidic lasers and their applications in biochemical sensing.

Optofluidic laser (OFL) technology, as an emerging technology combining microfluidics and laser technology, offers many unique advantages in sensing applications and has become a research hotspot for highly-sensitive intracavity biochemical analysis. Biochemical sensors based on OFLs can detect changes in biochemical parameters by using significant changes in laser output characteristics, so as to achieve high detection sensitivity. Here, we provide an overview of OFLs with a focus on their constructions, the design of OFL-based biochemical sensors, and their applications in biochemical analysis. Firstly, the three elements of an OFL, including the optical microcavity, gain medium, and pump source, are described systematically. After explaining the basic principles and characterization of OFLs for biochemical sensing, the current research progress of OFL-based biochemical sensors is summarized and analyzed according to the combination of OFLs with different assay techniques. This is followed by a discussion of the research on OFLs at the level of biological macromolecules, cells, and tissues. Finally, in view of the applications of OFLs in the field of biochemical sensing, the current challenges and future development directions are briefly discussed.

Nitrogen removal from mature landfill leachate through enhanced Partial Nitrification-Anammox process in an innovative multi-stage fixed biofilm reactor.

In the current integrated PN/A method/process for mature landfill leachate treatment, microbial inhibition and low nitrogen removal capacity are the big barriers due to high ammonia concentration and low C/N. This study aimed to evaluate the performance of a high-rate nitrogen removal lab-scale reactor, which combines pre-denitrification and Partial Nitrification-Anammox (PN/A) in a multi-stage fixed biofilm reactor (MFBR), for mature landfill leachate treatment. A nitrogen removal efficiency (NRE) of 90.43 % and an average nitrogen removal rate (NRR) of 0.94 kg/m3·d were observed at an influent NH+ 4-N concentration of 2274.39 mg/L during the last operational phase. The nitrogen mass balance showed that the nitrogen concentration gradually decreases along the course, and nitrogen was mainly removed in the aerobic chambers, in which Anammox contributed to 86.4 % of the removed nitrogen, while the front anoxic chamber is mainly used to remove NO- 3-N from the recirculation. Redundancy analysis showed that the variation in NH+ 4-N concentration along the course was the main factor affecting microbial community succession, which shows that the reactor configuration enables efficient cooperation and distribution of different microorganisms. Moreover, economic analysis of MFBR process showed that the energy consumption and carbon addition were reduced by 58.9 % and 100 %, respectively. Therefore, the MFBR established in this study, with its new configuration, achieves efficient treatment of landfill leachate in a single reactor and is environmentally friendly, and could be considered as a reference for full-scale landfill leachate treatment.

Erratum: PDLSCs Regulate Angiogenesis of Periodontal Ligaments via VEGF Transferred by Exosomes in Periodontitis: Erratum.

[This corrects the article DOI: 10.7150/ijms.40918.].

Mesenchymal stem cell-derived exosomes: A novel and potential remedy for cutaneous wound healing and regeneration.

Poor healing of cutaneous wounds is a common medical problem in the field of traumatology. Due to the intricate pathophysiological processes of wound healing, the use of conventional treatment methods, such as chemical molecule drugs and traditional dressings, have been unable to achieve satisfactory outcomes. Within recent years, explicit evidence suggests that mesenchymal stem cells (MSCs) have great therapeutic potentials on skin wound healing and regeneration. However, the direct application of MSCs still faces many challenges and difficulties. Intriguingly, exosomes as cell-secreted granular vesicles with a lipid bilayer membrane structure and containing specific components from the source cells may emerge to be excellent substitutes for MSCs. Exosomes derived from MSCs (MSC-exosomes) have been demonstrated to be beneficial for cutaneous wound healing and accelerate the process through a variety of mechanisms. These mechanisms include alleviating inflammation, promoting vascularization, and promoting proliferation and migration of epithelial cells and fibroblasts. Therefore, the application of MSC-exosomes may be a promising alternative to cell therapy in the treatment of cutaneous wounds and could promote wound healing through multiple mechanisms simultaneously. This review will provide an overview of the role and the mechanisms of MSC-derived exosomes in cutaneous wound healing, and elaborate the potentials and future perspectives of MSC-exosomes application in clinical practice.

Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes.

Apoptosis is a naturally occurring process generating plenty of apoptotic vesicles (apoVs), but the feature, fate and function of apoVs remain largely unknown. Notably, as an appealing source for cell therapy, mesenchymal stem cells (MSCs) undergo necessary apoptosis and release apoVs during therapeutic application. In this study, we characterized and used MSC-derived apoVs to treat type 2 diabetes (T2D) mice, and we found that apoVs were efferocytosed by macrophages and functionally modulated liver macrophage homeostasis to counteract T2D. We showed that apoVs can induce macrophage reprogramming at the transcription level in an efferocytosis-dependent manner, leading to inhibition of macrophage accumulation and transformation of macrophages towards an anti-inflammation phenotype in T2D liver. At the molecular level, we discovered that calreticulin (CRT) was exposed on the surface of apoVs to act as a critical 'eat-me' signal mediating apoV efferocytosis and macrophage regulatory effects. Importantly, we demonstrated that CRT-mediated efferocytosis of MSC-derived apoVs contributes to T2D therapy with alleviation of T2D phenotypes including glucose intolerance and insulin resistance. These findings uncover that functional efferocytosis of apoVs restores liver macrophage homeostasis and ameliorates T2D.

Expression of tricellular tight junction proteins and the paracellular macromolecule barrier are recovered in remission of ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) has a relapsing and remitting pattern, wherein the underlying mechanisms of the relapse might involve an enhanced uptake of luminal antigens which stimulate the immune response. The tricellular tight junction protein, tricellulin, takes charge of preventing paracellular passage of macromolecules. It is characterized by downregulated expression in active UC and its correct localization is regulated by angulins. We thus analyzed the tricellulin and angulin expression as well as intestinal barrier function and aimed to determine the role of tricellulin in the mechanisms of relapse. METHODS: Colon biopsies were collected from controls and UC patients who underwent colonoscopy at the central endoscopy department of Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin. Remission of UC was defined basing on the clinical appearance and a normal Mayo endoscopic subscore. Intestinal barrier function was evaluated by electrophysiological and paracellular flux measurements on biopsies mounted in Ussing chambers. RESULTS: The downregulated tricellulin expression in active UC was recovered in remission UC to control values. Likewise, angulins were in remission UC at the same levels as in controls. Also, the epithelial resistance which was decreased in active UC was restored in remission to the same range as in controls, along with the unaltered paracellular permeabilities for fluorescein and FITC-dextran 4 kDa. CONCLUSIONS: In remission of UC, tricellulin expression level as well as intestinal barrier functions were restored to normal, after they were impaired in active UC. This points toward a re-sealing of the impaired tricellular paracellular pathway and abated uptake of antigens to normal rates in remission of UC.

Leptin Downregulates Angulin-1 in Active Crohn's Disease via STAT3.

Crohn's disease (CD) has an altered intestinal barrier function, yet the underlying mechanisms remain to be disclosed. The tricellular tight junction protein tricellulin is involved in the maintenance of the paracellular macromolecule barrier and features an unchanged expression level in CD but a shifted localization. As angulins are known to regulate the localization of tricellulin, we hypothesized the involvement of angulins in CD. Using human biopsies, we found angulin-1 was downregulated in active CD compared with both controls and CD in remission. In T84 and Caco-2 monolayers, leptin, a cytokine secreted by fat tissue and affected in CD, decreased angulin-1 expression. This effect was completely blocked by STAT3 inhibitors, Stattic and WP1066, but only partially by JAK2 inhibitor AG490. The effect of leptin was also seen at a functional level as we observed in Caco-2 cells an increased permeability for FITC-dextran 4 kDa indicating an impaired barrier against macromolecule uptake. In conclusion, we were able to show that in active CD angulin-1 expression is downregulated, which leads to increased macromolecule permeability and is inducible by leptin via STAT3. This suggests that angulin-1 and leptin secretion are potential targets for intervention in CD to restore the impaired intestinal barrier.

Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss.

BACKGROUND: Bone mass loss in aging is linked with imbalanced lineage differentiation of bone marrow mesenchymal stem cells (BMMSCs). Recent studies have proved that histone deacetylases (HDACs) are regarded as key regulators of bone remodeling. However, HDACs involve in regulating BMMSC bio-behaviors remain elusive. Here, we investigated the ability of HDAC9 on modulation of autophagy and its significance in lineage differentiation of BMMSCs. METHODS: The effects of HDAC9 on lineage differentiation of BMMSCs and autophagic signaling were assessed by various biochemical (western blot and ChIP assay), morphological (TEM and confocal microscopy), and micro-CT assays. RESULTS: Sixteen-month mice manifested obvious bone mass loss and marrow fat increase, accompanied with decreased osteogenic differentiation and increased adipogenic differentiation of BMMSCs. Further, the expression of HDAC9 elevated in bone and BMMSCs. Importantly, HDAC9 inhibitors recovered the lineage differentiation abnormality of 16-month BMMSCs and reduced p53 expression. Mechanistically, we revealed that HDAC9 regulated the autophagy of BMMSCs by controlling H3K9 acetylation in the promoters of the autophagic genes, ATG7, BECN1, and LC3a/b, which subsequently affected their lineage differentiation. Finally, HDAC9 inhibition improved endogenous BMMSC properties and promoted the bone mass recovery of 16-month mice. CONCLUSIONS: Our data demonstrate that HDAC9 is a key regulator in a variety of bone mass by regulating autophagic activity in BMMSCs and thus a potential target of age-related bone loss treatment.

PDLSCs Regulate Angiogenesis of Periodontal Ligaments via VEGF Transferred by Exosomes in Periodontitis.

Abnormal angiogenesis is one of the significant features in periodontitis leading to progressive inflammation, but angiogenic changes of periodontal ligaments under inflammatory condition were rarely reported. Periodontal ligament stem cells (PDLSCs) were a kind of dental stem cells associated with vascularization. Here we investigated the alteration of angiogenesis of periodontal ligament in periodontitis, and revealed an exosome-mediated pathway to support the effect of PDLSCs on angiogenic improvement. Vascular specific marker CD31 and VEGFA were found to be highly expressed in periodontal ligaments of periodontitis. The VEGFA expression was up-regulated in inflamed PDLSCs compared to control, meanwhile the tube formation of HUVECs was improved when co-cultured with inflamed PDLSCs. Exosomes secretion of PDSLCs was augmented by inflammation, and promoted angiogenesis of HUVECs, whereas blocking secretion of exosomes led to degenerated angiogenesis of HUVECs. Exosome-trasferred VEGFA was proven to be the crucial communicator between PDLSCs and HUVECs. Inflammation inhibited miR-17-5p expression of PDLSCs and relieved its target VEGFA. However, overexpression of miR-17-5p blocked the pro-angiogenic ability of inflamed PDLSCs. In conclusion, the findings indicated that vascularization of periodontal ligaments was enhanced, and inflammatory micro-environment of periodontitis facilitated pro-angiogenesis of PDLSCs through regulating exosome-mediated transfer of VEGFA, which was targeted by miR-17-5p.

Effect of Airy Gaussian vortex beam array on reducing intermode crosstalk induced by atmospheric turbulence.

Vortex beam carrying angular momentum (OAM) will be disturbed by the random fluctuation of the refraction index of turbulent atmosphere, resulting in intermodal crosstalk among the different OAM modes. Recent advances have demonstrated that the employment of the abruptly autofocusing vortex beams can potentially mitigate the crosstalk effect. In this paper, a new type of abruptly autofocusing vortex beams, called Airy Gaussian vortex beam array (AGVBA) is proposed. By means of multi-plane wave optics simulation, the degradation of signal mode for AGVBA propagating through isotropic atmospheric turbulence is studied. In a comparison with the conventional abruptly autofocusing vortex beams, such as the ring Airy vortex beam (RAVB) and the Airy vortex beam array (AVBA), it is shown that AGVBA achieves more centralized intensity as well as a larger spot at the focal plane, thus can effectively balance the beam spreading and beam wander effect, resulting in mitigation of intermodal crosstalk.

Ficolin-A/2, acting as a new regulator of macrophage polarization, mediates the inflammatory response in experimental mouse colitis.

Human ficolin-2 (FCN-2) and mouse ficolin-A (FCN-A, a ficolin-2-like molecule in mouse) are activators of the lectin complement pathway, present in normal plasma and usually associated with infectious diseases, but little is known about the role of FCN-A/2 in inflammatory bowel disease (IBD). In our present study, we found that patients with IBD exhibited much higher serum FCN-2 levels than healthy controls. In the dextran sulphate sodium-induced acute colitis mouse model, FCN-A knockout mice showed much milder disease symptoms with less histological damage, lower expression levels of pro-inflammatory cytokines [interleukin-6 (IL-6), IL-1ß and tumour necrosis factor-α (TNF-α)], chemokines (CXCL1/2/10 and CCL4) and higher levels of the anti-inflammatory cytokine IL-10 compared with wild-type mice. We demonstrated that FCN-A/2 exacerbated the inflammatory pathogenesis of IBD by stimulating M1 polarization through the TLR4/MyD88/MAPK/NF-κB signalling pathway in macrophages. Hence, our data suggest that FCN-A/2 may be used as a novel therapeutic target for IBD.

Decreased Endomorphin-2 and µ-Opioid Receptor in the Spinal Cord Are Associated with Painful Diabetic Neuropathy.

Painful diabetic neuropathy (PDN) is one of the most common complications in the early stage of diabetes mellitus (DM). Endomorphin-2 (EM2) selectively activates the µ-opioid receptor (MOR) and subsequently induces antinociceptive effects in the spinal dorsal horn. However, the effects of EM2-MOR in PDN have not yet been clarified in the spinal dorsal horn. Therefore, we aimed to explore the role of EM2-MOR in the pathogenesis of PDN. The main findings were the following: (1) streptozotocin (STZ)-induced diabetic rats exhibited hyperglycemia, body weight loss and mechanical allodynia; (2) in the spinal dorsal horn, the expression levels of EM2 and MOR decreased in diabetic rats; (3) EM2 protein concentrations decreased in the brain, lumbar spinal cord and cerebrospinal fluid (CSF) in diabetic rats but were unchanged in the plasma; (4) the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) was significantly higher in diabetic rats than in control rats; and (5) intrathecal injection of EM2 for 14 days in the early stage of PDN partially alleviated mechanical allodynia and reduced MOR expression in diabetic rats. Our results demonstrate that the EM2-MOR signal may be involved in the early stage of PDN.

Alterations in the neural circuits from peripheral afferents to the spinal cord: possible implications for diabetic polyneuropathy in streptozotocin-induced type 1 diabetic rats.

Diabetic polyneuropathy (DPN) presents as a wide variety of sensorimotor symptoms and affects approximately 50% of diabetic patients. Changes in the neural circuits may occur in the early stages in diabetes and are implicated in the development of DPN. Therefore, we aimed to detect changes in the expression of isolectin B4 (IB4, the marker for nonpeptidergic unmyelinated fibers and their cell bodies) and calcitonin gene-related peptide (CGRP, the marker for peptidergic fibers and their cell bodies) in the dorsal root ganglion (DRG) and spinal cord of streptozotocin (STZ)-induced type 1 diabetic rats showing alterations in sensory and motor function. We also used cholera toxin B subunit (CTB) to show the morphological changes of the myelinated fibers and motor neurons. STZ-induced diabetic rats exhibited hyperglycemia, decreased body weight gain, mechanical allodynia and impaired locomotor activity. In the DRG and spinal dorsal horn, IB4-labeled structures decreased, but both CGRP immunostaining and CTB labeling increased from day 14 to day 28 in diabetic rats. In spinal ventral horn, CTB labeling decreased in motor neurons in diabetic rats. Treatment with intrathecal injection of insulin at the early stages of DPN could alleviate mechanical allodynia and impaired locomotor activity in diabetic rats. The results suggest that the alterations of the neural circuits between spinal nerve and spinal cord via the DRG and ventral root might be involved in DPN.

Down-regulation of insulin signaling is involved in painful diabetic neuropathy in type 2 diabetes.

BACKGROUND: Previous theories considered that the main cause of painful diabetic neuropathy (PDN) was due to hyperglycemia. However, recent evidence indicated that hyperinsulinemia plays a greater role in type 2 diabetic metabolisms (T2DM). OBJECTIVES: Our aim was to explore insulin signaling to determine the molecular mechanism involved in the pathogenesis of PDN in T2DM. STUDY DESIGN: A randomized, double blind, controlled animal trial. METHODS: We observed the localization of insulin receptor (IR) and phosphorylated insulin receptor substrate 1 (IRS-1) in the spinal cord using in situ hybridization and immunohistochemistry. Then we investigated the alternations of IR and pIRS-1 and the activity of the JAK2/STAT3 pathway by immunohistochemistry, Western Blotting, and cell culture. Finally, we detected the influence of intrathecal JAK2/STAT3 inhibitor (AG490) on nociceptive behavior and insulin signaling in ob/ob mice using Western Blotting. RESULTS: We found that IR and pIRS-1 are mainly located in neurons in the superficial layer of the spinal dorsal horn. The expressions of IR and pIRS-1 decreased and the JAK2/STAT3 pathway activated in the spinal dorsal horn in ob/ob mice with mechanical hyperalgesia. Next, our in vitro RESULTS indicated that hyperinsulinemia and hyperglycemia impaired insulin signaling along with the activated JAK2/STAT3 pathway in differentiated human neuronal cells (SH-SY5Y). Treatment through intrathecal injection of AG490, an inhibitor of the JAK2/STAT3 pathway, alleviated mechanical hyperalgesia in ob/ob mice and prevented impaired insulin signaling in the spinal cord. LIMITATIONS: The activation of the JAK2/STAT3 pathway could not explain the mechanism of PDN in T1DM.   CONCLUSIONS: We demonstrate that insulin signaling impairment in the spinal dorsal horn is associated with the activated JAK2/STAT3 pathway, which contributes to the progressive PDN in T2DM.

Initial identification of heavy metals contamination in Taihu Lake, a eutrophic lake in China.

A detailed investigation of seven heavy metals (Cu, Cd, Cr, As, Pb, Zn, Ni) in the water column, interstitial water and surface sediment was conducted to quantify the extent of their contamination in Taihu Lake. Results showed the average total concentrations ranged from 0.93 microg/L for Cd to 47.03 microg/L for Zn. The dissolved concentrations in the overlying water ranged from 0.06 microg/L for Cd to 15.86 microg/L for Zn. The metals in the Taihu Lake surface water were primarily in the particulate phase, especially for Cd, whose particulate concentration represented 94.3% of the total. In the surface sediment, the mean concentrations for Cr, Ni, Cu, Zn, As, Cd and Pb were 41.50, 28.72, 27.82, 65.46, 5.94, 0.82 and 41.17 mg/kg, respectively. The metals in the water column and sediments of Taihu Lake displayed significant spatial variations, and the higher metal concentrations mainly occurred in the north and west of Taihu Lake, especially in Zhushan Bay and West Taihu Lake. A quality assessment indicated that most of the metals in the surface water of Taihu Lake had no or low adverse health effects on organisms, except for Pb and Cu, which may cause chronic toxicity. Compared with the "Consensus-Based Sediment Quality Guidelines", the polluting metals were Cr, Ni and Cd, and the polluted regions were confined to Zhushan Bay, Meiliang Bay and the west of Taihu Lake, especially for north of Zhushan Bay. The polluted areas for Cr, Ni and Cd were 14.36, 34.70 and 13.24 km2, respectively. We suggest that Cr, Ni, and Cd in the polluted areas should be addressed and that tissue chemistry and sediment toxicity assessments be performed as soon as possible.