Xiaofeng Shen

Epidural analgesia in the latent phase of labor and the risk of cesarean delivery: a five-year randomized controlled trial.

Background:The optimal timing of epidural analgesia has been a controversial issue, and how early women can benefit from epidural analgesia is still debated. The objective of this trial was to test the hypothesis that patient-controlled epidural analgesia given at cervical dilation of 1.0 cm or more does not increase the risk of prolonged labor or Cesarean delivery. Methods:After institutional review board approval and patient consent, 12,793 nulliparous patients requesting neuraxial analgesia were enrolled and randomized to an early epidural (cervical dilation at least 1.0 cm) or delayed epidural (cervical dilation at least 4.0 cm) group. A 15-ml epidural analgesic mixture consisting of 0.125% (1.25 mg/ml) ropivacaine plus 0.3 &mgr;g/ml sufentanil was given in a single bolus, followed by patient-controlled pump with a 10-ml bolus without background infusion. Repeatable meperidine (25 mg) was prescribed as being the rescue analgesic to patients in the delayed epidural group. The primary outcome was the rate of Cesarean section. Results:The median diameters of cervical dilation were 1.6 cm and 5.1 cm in the early and delayed epidural groups, respectively (P < 0.0001). The duration of labor from analgesia request to vaginal delivery was equal in both groups (11.3 ± 4.5 h for early epidural and 11.8 ± 4.9 h for delayed epidural group women, P = 0.90). No statistically significant difference in the rate of Cesarean section was observed between the two groups on the intention-to-treat analysis (23.2% vs. 22.8% in the early and delayed epidural groups, respectively; P = 0.51). Conclusions:Epidural analgesia in the latent phase of labor at cervical dilation of 1.0 cm or more does not prolong the progression of labor and does not increase the rate of Cesarean in nulliparous women compared with the delayed analgesia at the cervical dilation of 4.0 cm or more.

Early life exposure to sevoflurane impairs adulthood spatial memory in the rat

Sevoflurane is a general anesthetic commonly used in the pediatric setting because it is sweet-smelling, nonflammable, fast acting and has a very short recovery time. Although recent clinical data suggest that early anesthesia exposure is associated with subsequent learning and memory problems, it is difficult to determine the exact scope of developmental neurotoxicity associated with exposure to specific anesthetics such as sevoflurane. This is largely due to inconsistencies in the literature. Thus, in the present studies we evaluated the effect of early life exposure to sevoflurane (1%, 2%, 3% or 4%) on adulthood memory impairment in Sprague-Dawley rats. Animals were exposed to different regimens of sevoflurane anesthesia on postnatal days (PNDs) 3, 7, or 14 or at 7 weeks (P7W) of age and spatial memory performance was assessed in adulthood using the Morris Water Maze (MWM). Rats exposed to sevoflurane exhibited significant memory impairment which was concentration and exposure duration dependent. Disruption of MWM performance was more severe in animals exposed on both PNDs 3 and 7 than in animals exposed on both PNDs 3 and 14. The younger the animals age at the time of exposure, the more significant the effect on later MWM performance. Compared to the neonates, animals exposed at P7W were relatively insensitive to sevoflurane: memory was impaired in this group only after repeated exposures to low doses or single exposures to high doses. Early life exposure to sevoflurane can result in spatial memory impairments in adulthood and the shorter the interval between exposures, the greater the deficit.

Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats

&NA; Pro‐inflammatory cytokine production after nociceptive stimuli is pivotal for hyperalgesia. As macrophage migration inhibitory factor (MIF), a pleiotropic cytokine produced mainly by nonneuronal tissue, has been involved in the regulation of neuronal functions, herein we examined the role for MIF in formalin‐induced inflammatory pain model. MIF critically contributed to nociceptive behaviors following formalin injection. Specifically, spinal administration of a MIF inhibitor (ISO‐1) prevented and reversed flinching responses in rats. Further examination showed that levels of both MIF and the MIF receptor CD74 were substantially increased within the ipsilateral spinal cord dorsal horn after formalin administration. Mechanistic studies revealed that MIF upregulated the expression of the spinal NMDA receptor subunit NR2B via the MAPK signaling pathway. Moreover, microglial cells were found to be the major source of spinal MIF after formalin administration by fluorescence colocalization. These data highlight spinal MIF plays a critical role in the pathogenesis of formalin‐induced inflammatory pain and suggest MIF may be a potential target for therapy of such pathological condition.

Spinal macrophage migration inhibitory factor is a major contributor to rodent neuropathic pain-like hypersensitivity.

Background:Neuropathic pain-like hypersensitivity evoked by peripheral nerve injury is a salient clinical feature of pathologic pain; however, the underlying mechanisms of this condition remain largely unknown. Previous work has confirmed that spinal macrophage migration inhibitory factor (MIF) contributes to the pathogenesis of formalin-induced inflammatory hyperalgesia, but the role for MIF in neuropathic pain is still not well defined. Methods:After approval by the Ethical Committee of Animal Use and Care, the sciatic chronic constriction nerve injury-induced rodent model of neuropathic pain was built. The mechanical threshold with von Frey hairs and thermal latency with hot plate were measured, and the expression of spinal MIF, CD74, and downstream extracellular signal-regulated kinase 1/2 signaling cascade was detected. Finally, MIF gene mutation and exogenous recombinant MIF were used for further clarification. Results:Intrathecal MIF tautomerase inhibitor reversed sciatic chronic constriction nerve injury-induced pain behaviors. The expression of MIF and CD74 up-regulated in a time-dependent manner in the ipsilateral spinal cord dorsal horn. These changes were associated with the activation of extracellular signal-regulated kinase 1/2 signaling by MIF/CD74 interaction, which subsequently led to up-regulatoin of interleukin-8 and N-methyl-d-aspartic acid receptor expression and additional production of prostaglandin E2. Further, MIF gene mutation and exogenous recombinant MIF could desensitize and mimic sciatic chronic constriction nerve injury-evoked pain responses and cellular changes, respectively. Conclusions:MIF-associated extracellular signal-regulated kinase 1/2-N-methyl-d-aspartic acid receptor or prostaglandin E2 cascade accounts for the changes in peripheral nerve injury-induced nociceptive responses.

Vascular dysfunction associated with type 2 diabetes and Alzheimer's disease: a potential etiological linkage.

The endothelium performs a crucial role in maintaining vascular integrity leading to whole organ metabolic homeostasis. Endothelial dysfunction represents a key etiological factor leading to moderate to severe vasculopathies observed in both Type 2 diabetic and Alzheimer’s Disease (AD) patients. Accordingly, evidence-based epidemiological factors support a compelling hypothesis stating that metabolic rundown encountered in Type 2 diabetes engenders severe cerebral vascular insufficiencies that are causally linked to long term neural degenerative processes in AD. Of mechanistic importance, Type 2 diabetes engenders an immunologically mediated chronic pro-inflammatory state involving interactive deleterious effects of leukocyte-derived cytokines and endothelial-derived chemotactic agents leading to vascular and whole organ dysfunction. The long term negative consequences of vascular pro-inflammatory processes on the integrity of CNS basal forebrain neuronal populations mediating complex cognitive functions establish a striking temporal comorbidity of AD with Type 2 diabetes. Extensive biomedical evidence supports the pivotal multi-functional role of constitutive nitric oxide (NO) production and release as a critical vasodilatory, anti-inflammatory, and anti-oxidant, mechanism within the vascular endothelium. Within this context, we currently review the functional contributions of dysregulated endothelial NO expression to the etiology and persistence of Type 2 diabetes-related and co morbid AD-related vasculopathies. Additionally, we provide up-to-date perspectives on critical areas of AD research with special reference to common NO-related etiological factors linking Type 2 diabetes to the pathogenesis of AD.

Postoperative Cognitive Dysfunction: Current Developments in Mechanism and Prevention

Postoperative cognitive dysfunction (POCD) is a subtle disorder of thought processes, which may influence isolated domains of cognition and has a significant impact on patient health. The reported incidence of POCD varies enormously due to lack of formal criteria for the assessment and diagnosis of POCD. The significant risk factors of developing POCD mainly include larger and more invasive operations, duration of anesthesia, advanced age, history of alcohol abuse, use of anticholinergic medications, and other factors. The release of cytokines due to the systemic stress response caused by anesthesia and surgical procedures might induce the changes of brain function and be involved in the development of postoperative cognitive dysfunction. The strategies for management of POCD should be a multimodal approach involving close cooperation between the anesthesiologist, surgeon, geriatricians, and family members to promote early rehabilitation and avoid loss of independence in these patients.

Remifentanil for labour analgesia: a double-blinded, randomised controlled trial of maternal and neonatal effects of patient-controlled analgesia versus continuous infusion

This trial aimed to compare the maternal and neonatal effects of remifentanil given by patient‐controlled analgesia (PCA) or continuous infusion for labour analgesia. Patient controlled analgesia was administered using increasing stepwise boluses from 0.1 to 0.4 μg.kg−1 (0.1 μg.kg−1 increment, 2 min lockout, n = 30). Continuous infusion used rates from 0.05 to 0.2 μg.kg−1.min−1 (0.05 μg.kg−1.min−1 increment, n = 30). Dose increments were given on request. Women reported lowest pain scores (median (IQR [range]) of 3 (2–4 [2–5]) for PCA and 4 (3–5.25 [3–7]) for continuous infusion (p = 0.004) at 60 min after the beginning of analgesia. The mean (SD) remifentanil umbilical vein/maternal artery ratio in the PCA and infusion groups were 0.74 (0.45) vs 0.70 (0.52), respectively (p = 0.776). The mean (SD) umbilical artery/umbilical vein ratios were 0.31 (0.12) vs 0.26 (0.07), respectively (p = 0.088). Maternal and neonatal adverse reactions of remifentanil were similar between the two groups. The total remifentanil consumption (median (IQR [range]) during PCA administration was lower than continuous infusion, 1.34 (1.22–1.48 [0.89–1.69]) mg vs 1.49 (1.35–1.61 [1.12–1.70] mg; p = 0.011). The results suggest that remifentanil PCA provides better pain relief and similar placental transfer compared with continuous infusion.

Macrophage migration inhibitory factor activates cyclooxygenase 2–prostaglandin E2 in cultured spinal microglia

In our previous study, peripheral inflammatory stimulation evoked production of macrophage migration inhibitory factor (MIF) in the spinal cord and found spinal microglia are the major source of MIF in this context. Given the contribution of the activated-microglia to the inflammatory neuropathy plus the role for upregulated COX 2 expression and PGE(2) production in the severity of clinical manifestations of these neuroinflammatory conditions, we herein tested the hypothesis that in vitro MIF stimulation to spinal microglia could result in an activation of COX 2-PGE(2) system by MIF-CD74 interaction. We found MIF played roles in evoking COX 2 mRNA and protein expression in a dose-dependent manner correspondingly in changes in PGE(2) level in the cultured rat microglia, but these changes could be inhibited by genetic deletion of CD74. Finally, MIF-induced COX 2-PGE(2) activation could be blocked by selective inhibitors of p44/p42 and p38 MAPKs. These data highlight MIF/CD74 interaction induces upregulation of COX 2 expression and PGE(2) secretion in primary rodent microglia, and further this effect is associated with downstream activation of p38 and p44/p42 signaling cascades, and favors the role of MIF as a novel pathway for microglia-associated neuroinflammation.

Menin regulates spinal glutamate-GABA balance through GAD65 contributing to neuropathic pain

BACKGROUND Our previous work found that tumor suppressor menin potentiates spinal synaptic plasticity in the context of peripheral nerve injury-induced neuropathic hypersensitivity, but the underlying molecular mechanisms are not clear. We hereby assessed the role of menin in regulating the spinal balance between glutamate and GABA and its contribution to the pathological condition of nerve injury-induced hypersensitivity. METHODS In spared nerve injury induced C57BL/6 mice, mechanical withdrawal threshold was measured with von Frey filaments after intrathecal administration of small interfering RNA (siRNA) of MEN1 or/and subcutaneous histone deacetylase (HDAC) inhibitors to control the level of glutamic acid decarboxylase 65 (GAD65). Immunoblotting and high-performance liquid chromatography were used to detect the level of protein expression and spinal glutamate and GABA, respectively. RESULTS Genetic knockdown of spinal menin alleviated nerve injury evoked mechanical hypersensitivity, which was strongly associated with the alteration of the spinal level of GAD65 that resulted in an imbalance of glutamate/GABA ratio from the baseline ratio of 5.8 ± 0.9 (×10(-4)) to the peak value of 58.6 ± 11.8 (×10(-4)) at the day 14 after SNI (p < 0.001), which was reversed by MEN1 siRNA to 14.7 ± 2.1 (×10(-4)) at the day 14 after nerve injury (p < 0.01). In further, selective inhibitors of HDACs considerably reversed the ratio of spinal glutamate and GABA, and also alleviated the mechanical withdrawal threshold markedly. CONCLUSION Our findings provide mechanistic insight into the contribution of the upregulated spinal menin to peripheral nerve injury induced neuropathic hypersensitivity by regulating glutamate-GABA balance through deactivating GAD65.

Tumor suppressor menin mediates peripheral nerve injury-induced neuropathic pain through potentiating synaptic plasticity

Synaptic plasticity is a crucial step in the development of central sensitization in the pathogenesis of neuropathic hyperalgesia. Menin, the product of the multiple endocrine neoplasia type 1 (MEN1) gene, possesses the property of synaptogenesis which plays an essential role in neuronal activity. We tested the contributing role of spinal menin in peripheral nerve injury-induced neuropathic hypersensitivity through modulating neuronal synaptic plasticity. After approval by the Institutional Animal Care and Use Committee, nociceptive responses were detected with von Frey filaments and thermal plate after spared nerve injury in C57BL/6 mice who were treated with either intrathecal antisense oligonucleotide of MEN1 (ASO) or vehicle. Extracellular spontaneous discharge frequency, field excitatory postsynaptic potential (fEPSP), and monosynaptic excitatory postsynaptic currents (EPSCs) were measured electrophysiologically. Intrathecal ASO alleviated nerve injury-induced mechanical and thermal hypersensitivity. Upregulated spinal menin after nerve injury colocalized with NeuN in the superficial laminae; genetic knockdown of spinal menin reduced nerve injury induced in vivo spontaneous activity and instantaneous frequency and in vitro field potentials; ASO decreased the frequency and amplitude of monosynaptic EPSCs, and reduced synaptic strength and total charge. Collectively, these findings highlight the role of upregulated neuronal menin in the spinal cord in potentiating spinal synaptic plasticity in peripheral nerve injury-induced neuropathic hypersensitivity.