Traumatic spinal cord injury (SCI) results in immediate tissue necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progressive hemorrhagic necrosis (PHN) and excessive excitation are the main sources of secondary neural injury. Recent approaches to attenuate PHN by glibenclamide can improve locomotor function after SCI. However, use of glibenclamide can exacerbate development of SCI-induced chronic pain by inhibiting K ATP channels to increase neuronal excitation and glial activation. In this study, we explored a treatment strategy involving administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals following spinal cord contusion. Our goal was to determine whether this combined approach enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult rats. We found that K ATP channels opener, diazoxide, decreased the hyperexcitability of primary sensory neurons after SCI by electrophysiology. Timed application of glibenclamide and diazoxide following contusion significantly improved locomotor function and mitigated development of SCI-induced chronic pain, as shown by behavioral evidence. Finally, we found that timed application of glibenclamide and diazoxide attenuates the inflammatory activity in the spinal cord and increases the survival of spinal matters following SCI. These preclinical studies introduce a promising potential treatment strategy to address SCI-induced dysfunction.
Mechanisms underlying chronic pain that develops after spinal cord injury (SCI) are incompletely understood. Most research on SCI pain mechanisms has focused on neuronal alterations within pain pathways at spinal and supraspinal levels associated with inflammation and glial activation. These events might also impact central processes of primary sensory neurons, triggering in nociceptors a hyperexcitable state and spontaneous activity (SA) that drive behavioral hypersensitivity and pain. SCI can sensitize peripheral fibers of nociceptors and promote peripheral SA, but whether these effects are driven by extrinsic alterations in surrounding tissue or are intrinsic to the nociceptor, and whether similar SA occurs in nociceptors in vivo are unknown. We show that small DRG neurons from rats (Rattus norvegicus) receiving thoracic spinal injury 3 d to 8 months earlier and recorded 1 d after dissociation exhibit an elevated incidence of SA coupled with soma hyperexcitability compared with untreated and sham-treated groups. SA incidence was greatest in lumbar DRG neurons (57%) and least in cervical neurons (28%), and failed to decline over 8 months. Many sampled SA neurons were capsaicin sensitive and/or bound the nociceptive marker, isolectin B4. This intrinsic SA state was correlated with increased behavioral responsiveness to mechanical and thermal stimulation of sites below and above the injury level. Recordings from C- and Aδ-fibers revealed SCI-induced SA generated in or near the somata of the neurons in vivo. SCI promotes the entry of primary nociceptors into a chronic hyperexcitable-SA state that may provide a useful therapeutic target in some forms of persistent pain.
OBJECTIVE To explore the risk factors for bacterial infections in the children with tumors and formulate targeted intervention measures.METHODS A total of 400 children with malignant tumors,who were treated in the hospital from Jul 2010 to Jul 2011,were enrolled in the study,then the incidence of bacterial infections and the infection sites were observed,the risk factors for the infections were analyzed,and the statistical analysis was performed with the use of SPSS17.0software.RESULTS The infections occurred in 105 of 400children with the infection rate of 26.3%,among whom the children with respiratory tract infections accounted for 48.6%,the patients with oral infections 17.1%.Totally 105 strains of pathogens have been isolated;the coagulase-negative Staphylococcus,Escherichia coli,and Pseudomonas aeruginosa ranked the top three species of pathogens,accounting for35.2%,27.6%,and 21.0%,respectively.The univariate analysis indicated that the incidence of infections was significantly higher in the children with less than 3years old,invasive operation,white blood cell counts less than2×109/L,neutrophils counts less than 0.5×109/L,or hospitalization duration more than 20 days than in other children,and there was significant difference(P0.05).The logistic regression analysis showed that the hospitalization duration more than 20 days,while blood cell counts less than 2×109/L,neutrophils counts no more than0.5×109/L,and invasive operation were the risk factors for the bacterial infections in the children with tumors after chemotherapy.CONCLUSIONThe incidence of bacterial infections is high in the children after chemotherapy;the risk factors for the infections include the hospitalization duration and invasive operation.It is necessary to take effective interventions in response to the risk factors so as to significantly reduce the incidence of bacterial infections in the children with tumors after the chemotherapy.
Cancer patients undergoing paclitaxel infusion usually experience peripheral nerve degeneration and serious neuropathic pain termed paclitaxel-induced peripheral neuropathy (PIPN). However, alterations in the dose or treatment schedule for paclitaxel do not eliminate PIPN, and no therapies are available for PIPN, despite numerous studies to uncover the mechanisms underlying the development/maintenance of this condition. Therefore, we aimed to uncover a novel mechanism underlying the pathogenesis of PIPN. Clinical studies suggest that acute over excitation of primary sensory neurons is linked to the pathogenesis of PIPN. We found that paclitaxel-induced acute hyperexcitability of primary sensory neurons results from the paclitaxel-induced inhibition of KCNQ potassium channels (mainly KCNQ2), found abundantly in sensory neurons and axons. We found that repeated application of XE-991, a specific KCNQ channel blocker, induced PIPN-like alterations in rats, including mechanical hypersensitivity and degeneration of peripheral nerves, as detected by both morphological and behavioral assays. In contrast, genetic deletion of KCNQ2 from peripheral sensory neurons in mice significantly attenuated the development of paclitaxel-induced peripheral sensory fiber degeneration and chronic pain. These findings may lead to a better understanding of the causes of PIPN and provide an impetus for developing new classes of KCNQ activators for its therapeutic treatment.
Abstract Opioids are the frontline analgesics in pain management. However, chronic use of opioid analgesics causes paradoxical pain that contributes to the decrease of their efficacy in pain control and the escalation of dose in long-term management of pain. The underling pathogenic mechanism is not well understood. Microglia have been commonly thought to play a critical role in the expression of opioid-induced hyperalgesia (OIH) in animal models. We performed microglial ablation experiments using either a genetic (CD11b-diphtheria toxin receptor transgenic mouse) or pharmacological (colony-stimulating factor 1 receptor inhibitor PLX5622) approaches. Surprisingly, ablating microglia using these specific and effective approaches did not cause detectable impairment in the expression of hyperalgesia induced by morphine. We confirmed this conclusion with behavioral test of mechanical and thermal hyperalgesia, in male and female mice, and with different species (mouse and rat). These findings raise caution about the widely assumed contribution of microglia to the development of OIH.
Cellular senescence has a complex role in lymphocyte carcinogenesis and drug resistance of lymphomas. Senescent lymphoma cells combine with immunocytes to create an ageing environment that can be reprogrammed with a senescence‑associated secretory phenotype, which gradually promotes therapeutic resistance. Certain signalling pathways, such as the NF‑κB, Wnt and PI3K/AKT/mTOR pathways, regulate the tumour ageing microenvironment and induce the proliferation and progression of lymphoma cells. Therefore, targeting senescence‑related enzymes or their signal transduction pathways may overcome radiotherapy or chemotherapy resistance and enhance the efficacy of relapsed/refractory lymphoma treatments. Mechanisms underlying drug resistance in lymphomas are complex. The ageing microenvironment is a novel factor that contributes to drug resistance in lymphomas. In terms of clinical translation, some senolytics have been used in clinical trials on patients with relapsed or refractory lymphoma. Combining immunotherapy with epigenetic drugs may achieve better therapeutic effects; however, senescent cells exhibit considerable heterogeneity and lymphoma has several subtypes. Extensive research is necessary to achieve the practical application of senolytics in relapsed or refractory lymphomas. This review summarises the mechanisms of senescence‑associated drug resistance in lymphoma, as well as emerging strategies using senolytics, to overcome therapeutic resistance in lymphoma.
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