Positive AMPA receptor modulation in the treatment of neuropsychiatric disorders: A long and winding road

Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Despite promising preclinical research, few direct and indirect AMPAR positive modulators have progressed past early clinical development. Challenges such as low potency have created barriers to effective implementation. Nevertheless, the functional complexity of AMPARs sets them apart from other drug targets and allows for specificity in drug discovery. Additional effective treatments for neuropsychiatric disorders that work through positive AMPAR modulation may eventually be developed.     

Peripheral and local anaesthetic techniques for paediatric surgery

Peripheral nerve blocks (PNBs) in paediatric patients are usually used as an adjunct to general anaesthesia, providing intra- and postoperative analgesia. These blocks provide good-quality analgesia preventing morbidity related to pain and reducing adverse effects from systemic analgesics. PNBs aid early patient recovery and discharge, which is essential in day-case surgery. Like all invasive techniques, PNBs are associated with complications and adverse effects. They should therefore be performed only after careful analysis of the risk:benefit ratio for each child. This article discusses a general approach to PNBs in children. It covers a small selection of limb and trunk blocks, and discusses the benefit of ultrasound guidance.     

The knowledge about autonomic dysreflexia among nursing and physiotherapy students

Context/Objective Autonomic dysreflexia is a clinical syndrome affecting persons with spinal cord lesions. The aim of the study was to detect the level of knowledge among students about autonomic dysreflexia in persons with spinal cord lesions.

Design: Single centre questionnaire study.

Setting: Faculty of Health Studies, Rijeka, Croatia.

Participants Nursing (n?=?43) and physiotherapy (n?=?48) students.

Outcome Measures: AD knowledge test.

Results: More of the half of the students (57%) had contact with persons with spinal cord lesions during work, especially nursing students. The self-estimated knowledge of autonomic dysreflexia was judged as poor or none in 73.6% of students. On the autonomic dysreflexia knowledge test, nursing students collected mean of 5.6 points and physiotherapy students 4.9 points (P?=?0.173). There was no difference in the autonomic dysreflexia test results regardless of work experience or group affiliation.

Conclusion: The level of knowledge about autonomic dysreflexia among students was low. Our results suggest the need for more education of students and health care professionals to apply adequate treatment to persons with episodes of autonomic dysreflexia.     

Microsurgical anatomy of the abducens nerve

The aim of this study is to demonstrate and review the detailed microsurgical anatomy of the abducens nerve and surrounding structures along its entire course and to provide its topographic measurements. Ten cadaveric heads were examined using ×3 to ×40 magnification after the arteries and veins were injected with colored silicone. Both sides of each cadaveric head were dissected using different skull base approaches to demonstrate the entire course of the abducens nerve from the pontomedullary sulcus to the lateral rectus muscle. The anatomy of the petroclival area and the cavernous sinus through which the abducens nerve passes are complex due to the high density of critically important neural and vascular structures. The abducens nerve has angulations and fixation points along its course that put the nerve at risk in many clinical situations. From a surgical viewpoint, the petrous tubercle of the petrous apex is an intraoperative landmark to avoid damage to the abducens nerve. The abducens nerve is quite different from the other nerves. No other cranial nerve has a long intradural path with angulations and fixations such as the abducens nerve in petroclival venous confluence. A precise knowledge of the relationship between the abducens nerve and surrounding structures has allowed neurosurgeon to approach the clivus, petroclival area, cavernous sinus, and superior orbital fissure without surgical complications. Clin. Anat. 25:1030–1042, 2012. © 2012 Wiley Periodicals, Inc.     

Preliminary Risk assessment for Acrylamide and Peripheral Neuropathy

Acrylamide (ACM) is a high-volume industrial chemical with diverse uses in manufacturing, construction and laboratory research. ACM is a well-established neurotoxic agent causing peripheral neuropathy with impairment in the arms and legs of exposed workers, most thoroughly studied in Swedish tunnel workers exposed to ACM grouting. A quantitative risk assessment was performed to assess ACM risk to workers. Using data from a published paper investigating peripheral neuropathies in Chinese chemical workers, estimates of exposure response for vibration perception threshold and nerve conduction velocities were calculated, based on hemoglobin adducts and air concentrations as exposure metrics. The benchmark dose procedure was applied in order to calculate excess risks of impairment, defined as adverse performance exceeding the 95^th percentile in unexposed populations, at various concentrations of airborne ACM exposure. Under the assumptions in this risk assessment, after three years of inhalation exposure at 0.3 mg/m³, the excess attributable impairment manifest in vibration perception and nerve conduction velocity is estimated to occur in 1-2% of workers. For 10 years at 0.3 mg/m³ ACM inhalation (equivalent to 3 years at 1.0 mg/m³) the excess prevalence of impairment would be 2-14% of workers, assuming the effect continues to accrue linearly in time. Using published data, the risks of impairment from peripheral neuropathy attributable to exclusively airborne ACM exposure can be predicted for exposure periods less than 10 years. The risks associated with dermal and airborne ACM exposures can be estimated by characterizing working process environments using ACM Hb-adduct levels and possibly monitored with urinary biomarkers.     

Intraoperative lateral rectus electromyographic recordings optimized by deep intraorbital needle electrodes

ObjectiveWe demonstrate the advantages and safety of long, intraorbitally-placed needle electrodes, compared to standard-length subdermal electrodes, when recording lateral rectus electromyography (EMG) during intracranial surgeries.MethodsInsulated 25 mm and uninsulated 13 mm needle electrodes, aimed at the lateral rectus muscle, were placed in parallel during 10 intracranial surgeries, examining spontaneous and stimulation-induced EMG activities. Postoperative complications in these patients were reviewed, alongside additional patients who underwent long electrode placement in the lateral rectus.ResultsIn 40 stimulation-induced recordings from 10 patients, the 25 mm electrodes recorded 6- to 26-fold greater amplitude EMG waveforms than the 13 mm electrodes. The 13 mm electrodes detected greater unwanted volume conduction upon facial nerve stimulation, typically exceeding the amplitude of abducens nerve stimulation. Except for one case with lateral canthus ecchymosis, no clinical or radiographic complications occurred in 36 patients (41 lateral rectus muscles) following needle placement.ConclusionsIntramuscular recordings from long electrode in the lateral rectus offers more reliable EMG monitoring than 13 mm needles, with excellent discrimination between abducens and facial nerve stimulations, and without significant complications from needle placement.SignificanceLong intramuscular electrode within the orbit for lateral rectus EMG recording is practical and reliable for abducens nerve monitoring.     

腹外斜肌的神经入肌点定位与肌内神经分布研究

目的　对人腹外斜肌的神经入肌点定位和肌内神经染色观察，为其临床应用提供形态学资料。 方法　成尸11具定位神经入肌点和5具行Sihler’s 肌内神经染色。 结果　腹外斜肌受下8对肋间神经外侧肌支支配，各个肌齿的神经入肌点距离相应肌齿起端中点(1.54±0.33)cm，位于锁骨中线与第5肋下缘的交界处至腋后线与第11肋下缘交界处的连线上。Sihler’s染色显示支配腹外斜肌的肋间神经外侧肌支入肌后分出小分支分布到各肌齿的起端1/3，然后约在各肌齿的近、中1/3交界处分出2支二级神经分支，即上支与下支，它们分出小分支分布到各肌齿的中间1/3，相邻两个肌齿的上支与下支在各肌齿中远部形成“U”形吻合，从“U”形吻合弓上分出小分支分布到各肌齿的止端1/3。在腹外斜肌上半部，各肌齿的神经分支分布到相应的肌齿，但在腹外斜肌下半部，上一肌齿的远侧下份是由下一肌齿的神经分支(上支)分布。 结论　①为临床上腹壁局部麻醉和术后切口疼痛的神经阻滞提供指导意义；②腹外斜肌中远部从上至下形成“波浪形”的神经分支密集区；③腹部手术切口建议不要超过四个肌齿。     

KDM6B epigenetically regulated-interleukin-6 expression in the dorsal root ganglia and spinal dorsal horn contributes to the development and maintenance of neuropathic pain following peripheral nerve injury in male rats

The lysine specific demethylase 6B (KDM6B) has been implicated as a coregulator in the expression of proinflammatory mediators, and in the pathogenesis of inflammatory and arthritic pain. However, the role of KDM6B in neuropathic pain has yet to be studied. In the current study, the neuropathic pain was determined by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) following lumbar 5 spinal nerve ligation (SNL) in male rats. Immunohistochemistry, Western blotting, qRT-PCR, and chromatin immunoprecipitation (ChIP)-PCR assays were performed to investigate the underlying mechanisms. Our results showed that SNL led to a significant increase in KDM6B mRNA and protein in the ipsilateral L4/5 dorsal root ganglia (DRG) and spinal dorsal horn; and this increase correlated a markedly reduction in the level of H3K27me3 methylation in the same tissue. Double immunofluorescence staining revealed that the KDM6B expressed in myelinated A- and unmyelinated C-fibers in the DRG; and located in neuronal cells, astrocytes, and microglia in the dorsal horn. Behavioral data showed that SNL-induced mechanical allodynia and thermal hyperalgesia were impaired by the treatment of prior to i.t. injection of GSK-J4, a specific inhibitor of KDM6B, or KDM6B siRNA. Both microinjection of AAV2-EGFP-KDM6B shRNA in the lumbar 5 dorsal horn and sciatic nerve, separately, alleviated the neuropathic pain following SNL. The established neuropathic pain was also partially attenuated by repeat i.t. injections of GSK-J4 or KDM6B siRNA, started on day 7 after SNL. SNL also resulted in a remarkable increased expression of interleukin-6 (IL-6) in the DRG and dorsal horn. But this increase was dramatically inhibited by i.t. injection of GSK-J4 and KDM6B siRNA; and suppressed by prior to microinjection of AAV2-EGFP-KDM6B shRNA in the dorsal horn and sciatic nerve. Results of ChIP-PCR assay showed that SNL-induced enhanced binding of STAT3 with IL-6 promoter was inhibited by prior to i.t. injection of GSK-J4. Meanwhile, the level of H3K27me3 methylation was also decreased by the treatment. Together, our results indicate that SNL-induced upregulation of KDM6B via demethylating H3K27me3 facilitates the binding of STAT3 with IL-6 promoter, and subsequently mediated-increase in the expression of IL-6 in the DRG and dorsal horn contributes to the development and maintenance of neuropathic pain. Targeting KDM6B might a promising therapeutic strategy to treatment of chronic pain.