Rong Shen

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.

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.

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

BACKGROUNDnOur 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.nnnMETHODSnIn 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.nnnRESULTSnGenetic 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.nnnCONCLUSIONnOur 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.

DNA Ploidy Cytometry Testing for Cervical Cancer Screening in China (DNACIC Trial): a Prospective Randomized, Controlled Trial

Purpose: This randomized, controlled trial was designed to determine whether the DNA cytometry testing is superior to the conventional cytologic testing for mass cervical cancer screening. Experimental Design: After approval by the institutional ethics review boards from three separate screening centers, a total of 23,993 Chinese women ages 20 to 65 years were randomly assigned into one of the two groups: a DNA cytometry testing group (11,999 women) and a cytologic testing group (11,994 women). Each woman underwent the other testing after first attending the assigned screening test. Women with positive results after assigned testing additionally underwent colposcopy and human papillomaviruses detections, and those with cervical precancerous or cancerous lesions received appropriate treatment. Sensitivity and specificity estimates were adjusted for verification bias. Analyses were by intention to treat and per protocol ways. Results: In the cytometric DNA testing group, cervical cancer was diagnosed in 40 subjects, compared with 24 subjects in the cytologic testing group [hazard ratio for the detection of advanced cancer in the DNA cytometry testing group, 0.42; 95% confidence interval (CI), 0.27-0.60]. The sensitivity of the DNA cytometry testing for cervical cancer was 91.7% (95% CI, 64.3-95.8), whereas the sensitivity of cytologic testing was 44.5% (95% CI, 25.2-61.3; P = 0.008). The specificity was 54.1% (95% CI, 31.6-69.0) for DNA cytometry testing and 70.6% (95% CI, 46.8-82.5; P = 0.003) for cytologic testing. The sensitivity of both tests used together was 100%, and the specificity was 91.8%. A total of 187 subjects reported mild to severe adverse events after treatment with positive results in 319 women. Conclusions: Our results highlight the benefit of the DNA cytometry testing strategy in mass cervical cancer screening with greater sensitivity and positive predicted value than the conventional cytologic testing in developing settings. (Clin Cancer Res 2009;15(20):6438–45)

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.

Epidemiology of multimorbidity

In their Article on the epidemiology of multimorbidity in Scotland (July 7, p 37), Karen Barnett and colleagues do not stratify the population studied according to ethnic group. We think that there could be important diff erences between such groups. Additionally, Barnett and col leagues analysed 40 long-term disorders, but they did not include obesity. Did the dataset from which Barnett and colleagues retrieved information for analysis contain basic demographic information such as weight and height? If it did, why did Barnett and colleagues not calculate body-mass index as an indicator of obesity and include it in their list of diseases? Given the increasing prevalence of obesity worldwide, we strongly believe it is a serious health problem in itself and contributes to the morbidity of other diseases. Finally, Barnett and colleagues showed that women had higher rates of multimorbidity than did men. This ratio might be artifi cially skewed if gynaecological diseases were included. So it would be better for physicians and policy makers if the results were analysed for men and women separately. Therefore, we propose that future studies should focus on a more complete list of diseases and stratify by race and sex.

Dopaminergic inhibition by G9a/Glp complex on tyrosine hydroxylase in nerve injury-induced hypersensitivity.

The neural balance between facilitation and inhibition determines the final tendency of central sensitization. Nerve injury-induced hypersensitivity was considered as the results from the enhanced ascending facilitation and the diminished descending inhibition. The role of dopaminergic transmission in the descending inhibition has been well documented, but its underlying molecular mechanisms are unclear. Previous studies demonstrated that the lysine dimethyltransferase G9a/G9a-like protein (Glp) complex plays a critical role in cocaine-induced central plasticity, and given cocaine’s role in the nerve system is relied on its function on dopamine system, we herein proposed that the reduced inhibition of dopaminergic transmission was from the downregulation of tyrosine hydroxylase expression by G9a/Glp complex through methylating its gene Th. After approval by the Animal Care and Use Committee, C57BL/6 mice were used for pain behavior using von Frey after spared nerve injury, and Th CpG islands methylation was measured using bisulfite sequencing at different nerve areas. The inhibitor of G9a/Glp, BIX 01294, was administered intraventricularly daily with bolus injection. The protein levels of G9a, Glp, and tyrosine hydroxylase were measured with immunoblotting. Dopamine levels were detected using high-performance liquid chromatography. The expression of G9a but not Glp was upregulated in ventral tegmental area at post-injury day 4 till day 49 (the last day of the behavioral test). Correspondingly, the Th CpG methylation is increased, but the tyrosine hydroxylase expression was downregulated and the dopamine level was decreased. After the intracerebroventriclar injection of BIX 01294 since the post-injury days 7 and 14 for consecutive three days, three weeks, and six weeks, the expression of tyrosine hydroxylase was upregulated with a significant decrease in Th methylation and increase in dopamine level. Moreover, the pain after G9a/Glp inhibitor was attenuated significantly. In sum, methytransferase G9a/Glp complex partially controls dopaminergic transmission by methylating Th in peripheral nerve injury-induced neuropathic pain.

Comparison Between the Use of Ropivacaine Alone and Ropivacaine With Sufentanil in Epidural Labor Analgesia.

AbstractTo compare the analgesic efficacy and safety of the sole local anesthetic ropivacaine with the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil given epidurally on the labor pain control.After institutional review board approval and patient consent, a total of 500 nulliparas requesting epidural labor analgesia were enrolled and 481 eventually were randomized into 2 groups: a sole local anesthetic group (ropivacaine 0.125%) and a combination of local anesthetic and opioidergic analgesic group (0.125% ropivacaineu200a+u200a0.3u200a&mgr;g/mL sufentanil). After the test dose, a 10-mL epidural analgesic solution was given in a single bolus, followed by intermittent bolus injection of 10 to 15u200amL of the solution. The primary outcome was the analgesic efficacy measured using Numerical Rating Scale (NRS) of pain. Other maternal and infant variables were evaluated as secondary outcomes.A total of 346 participants completed the study. The median NRS pain score during the 1st stage of labor was significantly lower in the combination group 2.2 (interquartile range [IQR]: 1.8–2.7) comparing to the sole local analgesic group 2.4 (IQR: 2.0–2.8) (Pu200a<u200a0.0001). No significant difference was observed in NRS pain score prior epidural analgesia and during the 2nd stage of labor. Patients in both groups rated same satisfaction of analgesia. Patients in the sole local analgesic group experienced fewer side effects than those in the combination group (37.7% vs 47.2%, Pu200a=u200a0.082). The individual analgesia-related cost in the sole local analgesic group was less (

DNA Cytometry Testing for Cervical Cancer Screening - Response

5.7u200a±u200a2.06) than that in the combination group (

A Perspective Analysis of Humanity in Medicine: How to Revive (Part II)

9.76u200a±u200a3.54) (Pu200a<u200a0.0001). The incidence of 1-minute Apgar ⩽ 7 was lower in the sole local analgesic group 2 (1.2%) than the combination group 10 (5.5%) (Pu200a=u200a0.038). No difference was found between other secondary outcomes.The sole local anesthetic ropivacaine produces a comparable labor analgesic effect as the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil at different stages of labor (&Dgr;NRSu200a=u200a0.2) but the former has less side effects, lower cost, and less incidence of lower 1-minute Apgar scoring. These results imply the necessity of a systematic reevaluation of epidural labor analgesia with sole local anesthetics against combination regimens of local anesthetics and other opioids.