Interaction of acute heart failure and acute kidney injury on in-hospital mortality of critically ill patients with sepsis: A retrospective observational study.

BACKGROUND: The present study aimed to evaluate the synergistic impact of acute heart failure (AHF) and acute kidney injury (AKI) on in-hospital mortality in critically ill patients with sepsis. METHODS: We undertook a retrospective, observational analysis using data acquired from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and eICU Collaborative Research Database (eICU-CRD). The effects of AKI and AHF on in-hospital mortality were examined using a Cox proportional hazards model. Additive interactions were analyzed using the relative extra risk attributable to interaction. RESULTS: A total of 33,184 patients were eventually included, comprising 20,626 patients in the training cohort collected from the MIMIC-IV database and 12,558 patients in the validation cohort extracted from the eICU-CRD database. After multivariate Cox analysis, the independent variables for in-hospital mortality included: AHF only (HR:1.20, 95% CI:1.02-1.41, P = 0.005), AKI only (HR:2.10, 95% CI:1.91-2.31, P < 0.001), and both AHF and AKI (HR:3.80, 95%CI:13.40-4.24, P < 0.001). The relative excess risk owing to interaction was 1.49 (95% CI:1.14-1.87), the attributable percentage due to interaction was 0.39 (95%CI:0.31-0.46), and the synergy index was 2.15 (95%CI:1.75-2.63), demonstrated AHF and AKI had a strong synergic impact on in-hospital mortality. And the findings in the validation cohort indicated identical conclusions to the training cohort. CONCLUSION: Our data demonstrated a synergistic relationship of AHF and AKI on in-hospital mortality in critically unwell patients with sepsis.

Neuronal complement cascade drives bone cancer pain via C3R mediated microglial activation.

Activation of spinal cord microglia is crucial for the development of bone cancer pain (BCP). The essential signal between neuronal excitability and microglial activation is not fully understood. In the present study, carcinoma implantation into tibia was used to induce BCP and RNAi-lentivirus was injected into spinal cord to knock down C1, C2 or C3 of complement cascade. We showed that C1, C2 and C3 co-localized in the same neurons and increased in cancer-bearing rats along with microglial activation. Knocked down of C1, C2 or C3 inhibited microglial activation and prevented the development of cancer-induced bone pain. Intrathecal administration of either minocycline (an inhibitor of microglial activity) to inhibit the activation of microglia or compstatin (a C3-targeted complement inhibitor) to block the complement cascade reversed cancer induced bone pain. Further study indicated that neuronal complement promoted the activation of microglia via complement 3 receptor (C3R). In the in vitro experiments, the proliferation of microglia was enhanced by the activation product of C3 (iC3b), but was inhibited by compstatin. These results indicated that neuronal complement pathway promoted the activation of microglia via C3R and contributed to the development of BCP.

Recombinant protein transduction domain-Cu/Zn superoxide dismutase alleviates bone cancer pain via peroxiredoxin 4 modulation and antioxidation.

Bone cancer pain (BCP) is a serious chronic clinical condition and reactive oxygen species (ROS) were considered to be involved in its development and persistency. Normally, superoxide dismutase (SOD) converts superoxide anions to hydrogen peroxide (H2O2) and H2O2 is then naturalized to be water by peroxiredoxin 4. We reported previously that recombinant protein transduction domain (PTD)-Cu/Zn SOD effectively scavenged excessive ROS and prevented cardiomyocytes from hypoxia-reoxygenation damage. However, whether PTD-Cu/Zn SOD would prevent BCP development is unknown. In the current study, we found that an implanted carcinoma in the rat tibia induced remarkable hyperalgesia, increased H2O2 levels and decreased SOD and peroxiredoxin 4 levels. After administration of recombinant PTD-Cu/Zn SOD to these tumor-burden rats, their hyperalgesia was significantly attenuated and peroxiredoxin 4 expression was significantly increased. In addition, an increased expression of N-methyl-d-aspartic acid (NMDA) receptors and a decreased expression of γ-aminobutyric acid (GABA) receptors in this cancer pain were prevented by PTD-Cu/Zn SOD administration or peroxiredoxin 4 overexpression. Our data suggested that reactive oxygen species, at least in part, play a role in cancer metastatic pain development and persistency which can be attenuated by the adminstration of recombinant PTD-Cu/Zn SOD via the peroxiredoxin 4 modulation from oxidative stress.

Slit2/Robo1 promotes synaptogenesis and functional recovery of spinal cord injury.

Neuronal network reconstruction is a pivotal determinant for functional recovery after spinal cord injury (SCI), the process of which includes synaptogenesis. Slit2 protein has been identified as a key regulator of axon regeneration and synapse formation in the vertebrate. Meanwhile, RhoA is the converging cascade of inhibitory molecules that interrupt synaptic plasticity in SCI. In the present study, we investigated the interaction among Slit2, Robo1, and RhoA and the potential roles of Slit2 in the pathological process of SCI. We showed that Slit2 was decreased, whereas Robo1 and RhoA were increased in the same surviving neurons in the spinal cord following SCI. We also found that inhibition of Slit2 led to upregulation of the expression of Robo1 and RhoA. However, the severe dysfunctions of the locomotor performance induced by SCI were reversed by treatments of Slit2-N, the active portion of Slit2, knockdown of Robo1 by the RNAi lentivirus, or inhibition of RhoA by the C3 exoenzyme, respectively. Further results suggested that downregulation of Slit2 and therefore upregulation of Robo1 and RhoA inhibited the activity of growth cone and hindered the formation of new synapses of surviving neurons near the injury sites of the spinal cord following SCI. Our study indicated a new mechanism of deficiency of synaptogenesis during the development of SCI and provided a potential strategy for the treatment of SCI.

GPR30 disrupts the balance of GABAergic and glutamatergic transmission in the spinal cord driving to the development of bone cancer pain.

Cancer induced bone pain is a very complicated clinical pain states that has proven difficult to be treated effectively due to poorly understand of underlying mechanism, but bone cancer pain (BCP) seems to be enhanced by a state of spinal sensitization. In the present study, we showed that carcinoma tibia implantation induced notable pain sensitization and up-regulation of G-protein-coupled estrogen receptor (GPR30) in the spinal cord of rats which was reversed by GPR30 knockdown. Further studies indicated that upregulation of GPR30 induced by cancer implantation resulted in a select loss of γ-aminobutyric acid-ergic (GABAergic) neurons and functionally diminished the inhibitory transmission due to reduce expression of the vesicular GABA transporter (VGAT). GPR30 contributed to spinal cord disinhibition by diminishing the inhibitory transmission via upregulation of α1 subunit and downregulation of γ2 subunits. GPR30 also facilitated excitatory transmission by promoting functional up-regulation of the calcium/calmodulin-dependent protein kinase II α (CaMKII α) in glutamatergic neurons and increasing the clustering of the glutamate receptor subunit 1 (GluR1) subunit to excitatory synapse.Taken together, GPR30 contributed to the development of BCP by both facilitating excitatory transmission and inhibiting inhibitory transmission in the spinal cord. Our findings provide the new spinal disinhibition and sensitivity mechanisms underlying the development of bone cancer pain.