Pro-Con Debate: Superior Versus Inferior Triangle Needle Placement in Transforaminal Epidural Injections.

Although transforaminal epidural injections have long been used for radicular pain, there is no universal standard injection approach to the neural foramen. The intervertebral foramen and its surrounding structures comprise an anatomically sensitive area that includes bone and joint structures, the intervertebral disk, blood vessels (in particular, the radicular arteries), the epidural sheath, and the spinal nerve root. Given the relatively high risk of inadvertent injury or injection to these nearby structures, image guidance for transforaminal epidural steroid injections (TFESIs) is standard of care. However, there is a lack of consensus regarding the optimal approach to the neural foramen: from the traditional superior ("safe") triangle or from the inferior (Kambin's) triangle. In this Pro-Con commentary article, we discuss the relative advantages and disadvantages of each approach for TFESIs.

Knowledge Gaps in Anesthetic Gas Utilization in a Large Academic Hospital System: A Multicenter Survey.

Inhaled anesthetics account for a significant portion of the greenhouse gases generated by perioperative services within the healthcare systems. This cross-sectional study aimed to identify knowledge gaps and practice patterns related to carbon dioxide (CO2) absorbents and intraoperative delivery of fresh gas flows (FGF) for future sustainability endeavors. Secondary aims focused on differences in these knowledge gaps based on the level of training. Surveys were distributed at five large academic medical centers. In addition to site-specific CO2 absorbent use and practice volume and experience, respondents at each institution were queried about individual practice with FGF rates during anesthetic maintenance as well as the cost-effectiveness and environmental impact of different volatile anesthetics. Results were stratified and analyzed by the level of training. In total, 368 (44% physicians, 30% residents, and 26% nurse anesthetists) respondents completed surveys. Seventy-six percent of respondents were unaware or unsure about which type of CO2 absorbent was in use at their hospital. Fifty-nine percent and 48% of respondents used sevoflurane and desflurane with FGF ≥1 L/min, respectively. Most participants identified desflurane as the agent with the greatest environmental impact (89.9%) and a greater proportion of anesthesiologists correctly identified isoflurane as a cost-effective anesthetic (78.3%, p=0.02). Knowledge gaps about in-use CO2 absorbent and optimal FGF usage were identified within the anesthesia care team. Educational initiatives to increase awareness about the carbon emissions from anesthesia and newer CO2 absorbents will impact the environmental and economic cost per case and align anesthesia providers toward healthcare decarbonization.

The Skp1 Homologs SKR-1/2 Are Required for the Caenorhabditis elegans SKN-1 Antioxidant/Detoxification Response Independently of p38 MAPK.

SKN-1/Nrf are the primary antioxidant/detoxification response transcription factors in animals and they promote health and longevity in many contexts. SKN-1/Nrf are activated by a remarkably broad-range of natural and synthetic compounds and physiological conditions. Defining the signaling mechanisms that regulate SKN-1/Nrf activation provides insights into how cells coordinate responses to stress. Nrf2 in mammals is regulated in part by the redox sensor repressor protein named Keap1. In C. elegans, the p38 MAPK cascade in the intestine activates SKN-1 during oxidative stress by promoting its nuclear accumulation. Interestingly, we find variation in the kinetics of p38 MAPK activation and tissues with SKN-1 nuclear accumulation among different pro-oxidants that all trigger strong induction of SKN-1 target genes. Using genome-wide RNAi screening, we identify new genes that are required for activation of the core SKN-1 target gene gst-4 during exposure to the natural pro-oxidant juglone. Among 10 putative activators identified in this screen was skr-1/2, highly conserved homologs of yeast and mammalian Skp1, which function to assemble protein complexes. Silencing of skr-1/2 inhibits induction of SKN-1 dependent detoxification genes and reduces resistance to pro-oxidants without decreasing p38 MAPK activation. Global transcriptomics revealed strong correlation between genes that are regulated by SKR-1/2 and SKN-1 indicating a high degree of specificity. We also show that SKR-1/2 functions upstream of the WD40 repeat protein WDR-23, which binds to and inhibits SKN-1. Together, these results identify a novel p38 MAPK independent signaling mechanism that activates SKN-1 via SKR-1/2 and involves WDR-23.

Increased age reduces DAF-16 and SKN-1 signaling and the hormetic response of Caenorhabditis elegans to the xenobiotic juglone.

Cells adapt to stressors by activating mechanisms that repair damage and protect them from further injury. Stress-induced damage accumulates with age and contributes to age associated diseases. Increased age attenuates the ability to mount a stress response, but little is known about the mechanisms by which this occurs. To begin addressing this problem, we studied hormesis in the nematode Caenorhabditis elegans. When exposed to a low concentration of the xenobiotic juglone, young worms mount a robust hormetic stress response and survive a subsequent exposure to a higher concentration of juglone that is normally lethal to naïve animals. Old worms are unable to mount this adaptive response. Microarray and RNAi analyses demonstrate that an altered transcriptional response to juglone is responsible in part for the reduced adaptation of old worms. Many genes differentially regulated in young versus old animals are known or postulated to be regulated by the FOXO homologue DAF-16 and the Nrf2 homologue SKN-1. Activation of these pathways is greatly reduced in juglone stressed old worms. DAF-16- and SKN-1-like transcription factors play highly conserved roles in regulating stress resistance and longevity genes. Our studies provide a foundation for developing a molecular understanding of how age affects cytoprotective transcriptional pathways.

The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis elegans.

The transcription factor SKN-1 protects Caenorhabditis elegans from stress and promotes longevity. SKN-1 is regulated by diverse signals that control metabolism, development, and stress responses, but the mechanisms of regulation and signal integration are unknown. We screened the C. elegans genome for regulators of cytoprotective gene expression and identified a new SKN-1 regulatory pathway. SKN-1 protein levels, nuclear accumulation, and activity are repressed by the WD40 repeat protein WDR-23, which interacts with the CUL-4/DDB-1 ubiquitin ligase to presumably target the transcription factor for proteasomal degradation. WDR-23 regulates SKN-1 target genes downstream from p38 mitogen-activated protein kinase, glycogen synthase kinase 3, and insulin-like receptor pathways, suggesting that phosphorylation of SKN-1 may function to modify its interaction with WDR-23 and/or CUL-4/DDB-1. These findings define the mechanism of SKN-1 accumulation in the cell nucleus and provide a new mechanistic framework for understanding how phosphorylation signals are integrated to regulate stress resistance and longevity.

Long balloon angioplasty with focal stenting for the treatment of diffuse coronary artery disease.

The objective of this study was to evaluate the efficacy of treating long coronary lesions (> 30 mm) with either a 40 or a 60 mm long Scimed Cobra balloon followed by focal (contingency) stenting of areas with suboptimal results. Diffuse lesion length is a morphological characteristic associated with a poorer clinical outcome after balloon angioplasty with or without stenting. Patients were enrolled in a prospective randomized fashion to have initial PTCA with either a 40 or a 60 mm long balloon followed by focal stenting in areas with suboptimal results. The MACE rate at 6-month follow-up was collected from all patients and was the primary endpoint of the study. A total of 41 patients were enrolled into the study. The acute procedural success rate was 97.5% with a 6-month MACE rate of 9.8%. The use of long balloons with contingency stenting is a highly effective strategy for the treatment of diffuse coronary lesions.