RALY participates in nerve trauma-induced nociceptive hypersensitivity through triggering Eif4g2 gene expression in primary sensory neurons.

BACKGROUND AND PURPOSE: Peripheral nerve trauma-induced dysregulation of pain-associated genes in the primary sensory neurons of dorsal root ganglion (DRG) contributes to neuropathic pain genesis. RNA-binding proteins participate in gene transcription. We hypothesized that RALY, an RNA-binding protein, participated in nerve trauma-induced dysregulation of DRG pain-associated genes and nociceptive hypersensitivity. METHODS AND RESULTS: Immunohistochemistry staining showed that RALY was expressed exclusively in the nuclei of DRG neurons. Peripheral nerve trauma caused by chronic constriction injury (CCI) of unilateral sciatic nerve produced time-dependent increases in the levels of Raly mRNA and RALY protein in injured DRG. Blocking this increase through DRG microinjection of adeno-associated virus 5 (AAV5)-expressing Raly shRNA reduced the CCI-induced elevation in the amount of eukaryotic initiation factor 4 gamma 2 (Eif4g2) mRNA and Eif4g2 protein in injured DRG and mitigated the development and maintenance of CCI-induced nociceptive hypersensitivity, without altering basal (acute) response to noxious stimuli and locomotor activity. Mimicking DRG increased RALY through DRG microinjection of AAV5 expressing Raly mRNA up-regulated the expression of Eif4g2 mRNA and Eif4g2 protein in the DRG and led to hypersensitive responses to noxious stimuli in the absence of nerve trauma. Mechanistically, CCI promoted the binding of RALY to the promoter of Eif4g2 gene and triggered its transcriptional activity. CONCLUSION AND IMPLICATIONS: Our findings indicate that RALY participates in nerve trauma-induced nociceptive hypersensitivity likely through transcriptionally triggering Eif4g2 expression in the DRG. RALY may be a potential target in neuropathic pain management.

Protecting the Airway and the Physician: Lessons from 214 Cases of Endotracheal Intubation Litigation.

Objective: Medicolegal examination of an intervention as common as endotracheal intubation may be valuable to physicians in many specialties. Our objectives were to comprehensively detail the factors raised in litigation to better educate physicians on strategies for minimizing liability and augmenting patient safety. Methods: Publicly available court records were searched for pertinent litigation. Ultimately, 214 jury verdict and settlement reports were examined for various factors, including outcome, award, geographic location, defendant specialty, setting in which an injury occurred, patient demographics, and other causes of malpractice. Results: Ninety-two cases (43.0%) were resolved in the defendant's favor, with the remaining cases resulting in out-of-court settlement or a plaintiff's verdict. Payments from these cases were considerable, averaging $2.5 M. The most frequent physician defendants were anesthesiologists (59.8%) and emergency-physicians (19.2%), although other specialties were well represented. The most common setting of injury was the operating room (45.3%). Common factors included sustaining permanent deficits (89.2%), death (50.5%), and anoxic brain injury (37.4%). Injuries occurring in labor and delivery mostly involved newborns and had among the highest awards. Conclusions: Litigation involves injuries sustained in numerous settings. The most common factors present included sustaining permanent deficits, including anoxic brain injury. The presence of this latter injury increased the likelihood of a case being resolved with payment. Finally, deficits in informed consent were noted in numerous cases, stressing the importance of a clear process in which the physician explains specific risks (such as those detailed in this analysis), benefits, and alternatives.

Unexpected pro-injury effect of propofol on vascular smooth muscle cells with increased oxidative stress.

OBJECTIVES: Propofol is a widely used intravenous anesthetic agent with antioxidant properties. However, the effect of propofol on reactive oxygen species-induced injury in vascular smooth muscle cells is still unknown. In this study, the authors determined the effect of propofol on hydrogen peroxide-induced injury in vascular smooth muscle cells and the potential molecular mechanisms involved. DESIGN: Prospective cell and animal study. SETTING: University research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: For the in vitro study, rat vascular smooth muscle cells pretreated with vehicle or hydrogen peroxide (200 µM) were exposed to vehicle or increasing concentrations of propofol (10-50 µM). For the in vivo study, propofol (12 mg kg⁻¹/hr⁻¹, intravenous) or vehicle was administrated into rats after carotid artery angioplasty. MEASUREMENTS AND MAIN RESULTS: The cell survival and cell death were measured by MTT and trypan blue exclusion. Cell apoptosis was evaluated by terminal deoxynucleotide transferase dUTP nick end labeling staining and cleaved caspase-3 expression. To further elucidate the molecular mechanisms in propofol-mediated cellular effect, the expression of programmed cell death 4 and microRNA-21 were measured. Unexpectedly, propofol exacerbated hydrogen peroxide-induced injury responses in vascular smooth muscle cells as demonstrated by a decrease in cell viability and an increase in trypan blue-stained cells, cell apoptosis, and cleaved caspase-3 expression. In addition, propofol inhibited hydrogen peroxide-induced up-regulation of microRNA-21 and increased its target gene programmed cell death 4. Propofol-mediated injury was attenuated by restoration of microRNA-21 expression. Finally, the pro-injury effect of propofol on vascular cells with increased reactive oxygen species was illustrated in vivo in rat carotid arteries after angioplasty. CONCLUSIONS: The results revealed that propofol exacerbates cell injury in vascular smooth muscle cells with increased reactive oxygen species, at least in part, through microRNA-21 and its target gene, programmed cell death 4. Because increased reactive oxygen species is a common pathologic component in many vascular diseases, the novel findings in the current study suggest that propofol might have some application limitations.

A clinical prediction rule for pulmonary complications after thoracic surgery for primary lung cancer.

BACKGROUND: There is controversy surrounding the value of the predicted postoperative diffusing capacity of lung for carbon monoxide (DLCOppo) in comparison to the forced expired volume in 1 s for prediction of pulmonary complications (PCs) after thoracic surgery. METHODS: Using a prospective database, we performed an analysis of 956 patients who had resection for lung cancer at a single institution. PC was defined as the occurrence of any of the following: atelectasis, pneumonia, pulmonary embolism, respiratory failure, and need for supplemental oxygen at hospital discharge. RESULTS: PCs occurred in 121 of 956 patients (12.7%). Preoperative chemotherapy (odds ratio 1.64, 95% confidence interval 1.06-2.55, P = 0.02, point score 2) and a lower DLCOppo (odds ratio per each 5% decrement 1.13, 95% confidence interval 1.06-1.19, P < 0.0001, point score 1 per each 5% decrement of DLCOppo less than 100%) were independent risk factors for PCs. We defined 3 overall risk categories for PCs: low < or =10 points, 39 of 448 patients (9%); intermediate 11-13 points, 37 of 256 patients (14%); and high > or =14 points, 42 of 159 patients (26%). The median (range) length of hospital stay was significantly greater for patients who developed PCs than for those who did not: 12 (3-113) days vs 6 (2-39) days, P < 0.0001, respectively. Similarly, 30-day mortality was significantly more frequent for patients who developed PCs than for those who did not: 16 of 121 (13.2%) vs 6 of 835 (0.7%), P < 0.0001. CONCLUSIONS: These data show that PCs after thoracic surgery for lung cancer can be predicted with moderate accuracy based on DLCOppo and whether patients had chemotherapy. Forced expired volume in 1 s was not a predictor of PCs.