Motor-Sparing Effect of Adductor Canal Block for Knee Analgesia: An Updated Review and a Subgroup Analysis of Randomized Controlled Trials Based on a Corrected Classification System.

OBJECTIVE: Discrepancies in the definition of adductor canal block (ACB) lead to inconsistent results. To investigate the actual analgesic and motor-sparing effects of ACB by anatomically defining femoral triangle block (FTB), proximal ACB (p-ACB), and distal ACB (d-ACB), we re-classified the previously claimed ACB approaches according to the ultrasound findings or descriptions in the corresponding published articles. A meta-analysis with subsequent subgroup analyses based on these corrected results was performed to examine the true impact of ACB on its analgesic effect and motor function (quadriceps muscle strength or mobilization ability). An optimal ACB technique was also suggested based on an updated review of evidence and ultrasound anatomy. MATERIALS AND METHODS: We systematically searched studies describing the use of ACB for knee surgery. Cochrane Library, PubMed, Web of Science, and Embase were searched with the exclusion of non-English articles from inception to 28 February 2022. The motor-sparing and analgesic aspects in true ACB were evaluated using meta-analyses with subsequent subgroup analyses according to the corrected classification system. RESULTS: The meta-analysis includes 19 randomized controlled trials. Compared with the femoral nerve block group, the quadriceps muscle strength (standardized mean difference (SMD) = 0.33, 95%-CI [0.01; 0.65]) and mobilization ability (SMD = -22.44, 95%-CI [-35.37; -9.51]) are more preserved in the mixed ACB group at 24 h after knee surgery. Compared with the true ACB group, the FTB group (SMD = 5.59, 95%-CI [3.44; 8.46]) has a significantly decreased mobilization ability at 24 h after knee surgery. CONCLUSION: By using the corrected classification system, we proved the motor-sparing effect of true ACB compared to FTB. According to the updated ultrasound anatomy, we suggested proximal ACB to be the analgesic technique of choice for knee surgery. Although a single-shot ACB is limited in duration, it remains the candidate of the analgesic standard for knee surgery on postoperative day 1 or 2 because it induces analgesia with less motor involvement in the era of multimodal analgesia. Furthermore, data from the corrected classification system may provide the basis for future research.

Case Report: Anesthetic Management and Electrical Cardiometry as Intensive Hemodynamic Monitoring During Cheiloplasty in an Infant With Enzyme-Replaced Pompe Disease and Preserved Preoperative Cardiac Function.

Introduction: Pompe disease is caused by deficiency of the lysosomal enzyme acid α-glucosidase, which results in cardiac and muscular complications that can jeopardize perioperative outcomes. We report a 4-month-old infant with Pompe disease receiving cheiloplasty under general anesthesia with the aid of peripheral nerve blocks and intensive hemodynamic monitoring. Case Description: This case report describes a 4-month-old full-term Taiwanese female infant who presented with left unilateral cleft lip and palate in the prenatal examination. She was diagnosed with infantile-onset Pompe disease after acidic α-glucosidase (GAA) gene sequencing. She also received enzyme replacement therapy (ERT) 15 days after birth and regular ERT every other week. Cheiloplasty was performed under general anesthesia uneventfully, and peripheral nerve blocks were adopted for analgesia. Intensive hemodynamic monitoring using electrical cardiometry technology (ICON®) and pulse contour analysis (FloTrac system) were applied during the operation. No adverse effects were observed, and the wound healed well. Therefore, the patient was discharged 4 days after surgery. Conclusion: With the availability of ERT, severe organ dysfunction in infantile-onset Pompe disease patients is no longer common. However, moderate cardiac depression can still occur while increasing inspiratory pressure and deepening the anesthesia level despite a normal preoperative echocardiogram report. Therefore, careful, gradual titration is desirable. Furthermore, electrical cardiometry can detect hemodynamic changes more instantaneously and reliably than pulse contour analysis. In addition, we suggest taking advantage of the peripheral nerve block as a part of balanced anesthesia to alleviate the cardiac suppression caused by general anesthesia.

Operative hysteroscopy intravascular absorption syndrome is more than just the gynecological transurethral resection of the prostate syndrome: A case series and literature review.

OBJECTIVE: Operative hysteroscopy intravascular absorption (OHIA) syndrome refers to fluid overload complications from operative hysteroscopies. Despite guidelines for safe operative hysteroscopies, instances of OHIA syndrome have been reported. CASE REPORT: We reported three cases of OHIA syndrome. A 48-year-old female patient presented net irrigation fluid of 11,900 mL and developed severe metabolic acidosis, conscious disturbance, acute pulmonary edema, and unexpected intensive care unit admission. A 49-year-old female patient presented net irrigation fluid of 4500 mL and developed desaturation and acute pulmonary edema. A 45-year-old female patient presented net irrigation fluid of 2400 mL and developed hyponatremia, increased hilum lung marking, and prolonged postanesthesia care unit observation. CONCLUSION: For safety, clinicians should use isotonic electrolyte-containing distension media and bipolar electrosurgical instruments in operative hysteroscopies, and fluid status should be monitored closely, particularly at net and total irrigation amounts >3000 and > 8000 mL, respectively. Intrauterine pressure should also be minimized to reduce intravascular and intraperitoneal absorption.

Ultrasound-guided superior laryngeal nerve block assists in anesthesia for bronchoscopic surgical procedure: A case report of anesthesia for rigid bronchoscopy.

INTRODUCTION: Evolving techniques in the field of therapeutic bronchoscopy have led to the return of rigid bronchoscopy in the treatment of complex central airway disease. Rigid bronchoscopy is typically performed under general anesthesia because of the strong stimulation caused by metal instruments. Anesthesia for rigid bronchoscopy is challenging to administer because anesthesiologists and interventionists share the same working channel: the airway. Previously reviewed anesthetic methods are used primarily for short procedures. Balanced anesthesia with ultrasound-guided superior laryngeal nerve (SLN) block and total intravenous anesthesia might provide anesthesia for a prolonged procedure and facilitate patient recovery. PATIENT CONCERNS: A patient with obstructed endobronchial stent was referred for therapeutic rigid bronchoscopy, which requires deeper anesthesia than flexible bronchoscopy. There were concerns of the stronger stimulation of the rigid bronchoscopy, lengthy duration of the procedure, higher risk of hypoxemia, and the difficulty of mechanical ventilation weaning after anesthesia due to the patients co-morbidities. DIAGNOSIS: A 66-year-old female patient presented with a history of breast cancer with lung metastases. Right main bronchus obstruction due to external compression of lung metastases was relieved through insertion of an endobronchial stent, but obstructive granulation developed after 4 months. Presence of the malfunctioning stent caused severe cough and discomfort. Removal of the stent by using a flexible bronchoscope was attempted twice but failed. INTERVENTIONS: Regional anesthesia of the upper airway through ultrasound-guided SLN block combined with intratracheal 2% lidocaine spray was performed to assist in total intravenous anesthesia (TIVA) during rigid bronchoscopy. OUTCOMES: The patient maintained steady spontaneous breathing throughout the procedure without laryngospasm, bucking, or desaturation. Emergence from anesthesia was smooth and rapid after propofol infusion was discontinued. The surgery lasted 2.5 hours without discontinuity, and no perioperative pulmonary or cardiovascular complications were noted. CONCLUSION: Ultrasound-guided SLN block is a simple technique with a high success rate and low complication rate. Application of SLN block to assist TIVA provides sufficient anesthesia for lengthened therapeutic rigid bronchoscopy without interruption and facilitates patient recovery.

Renal insufficiency plays a crucial association factor in severe knee osteoarthritis-induced pain in patients with total knee replacement: A retrospective study.

Pain, the main symptom of osteoarthritis (OA), can lead to functional disability in patients with knee OA. Understanding the association factors related to knee pain is important since preventing OA-induced disabilities can be achieved by modifying these pain-associated issues. Therefore, this study was aimed to investigate the association factors for OA-induced knee pain in Taiwanese patients who received total knee replacements (TKR).In this retrospective study, 357 subjects who had undergone TKR at the Taipei Municipal Wan-Fang Hospital were recruited. The distribution of pain severity among patients with knee OA was evaluated. Demographic data and clinical parameters were analyzed to determine relationships between these variables and the severity of knee OA pain.Of the 357 patients studied, 54% and 33% had moderate and severe knee pain, respectively. Furthermore, a multivariate logistic regression analysis revealed that serum creatinine (>1.5 mg/dL) and an estimated glomerular filtration rate (eGFR) (<60 mL/min/1.73 m) were significantly associated with severe knee pain in OA patients. A significant correlation between severe knee pain and serum creatinine or eGFR was demonstrated by Pearson correlations.Taken together, the renal insufficiency defined by an elevated serum creatinine or a low eGFR in OA patients who required TKR was associated with severe knee pain. These variables must be considered while treating knee OA pain, especially in those patients with severe pain.

Sepsis-induced liver dysfunction was ameliorated by propofol via suppressing hepatic lipid peroxidation, inflammation, and drug interactions.

AIMS: Our previous study showed that propofol can protect against sepsis-induced insults through suppressing liver nitrosation and inflammation. This study further evaluated the mechanisms of propofol-caused protection from sepsis-induced liver dysfunction. MAIN METHODS: Male Wistar rats were subjected to cecal ligation and puncture (CLP) and then exposed to propofol. Levels of hepatic oxidative stress and lipid peroxidation were consecutively measured. Expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-4 messenger (m)RNA or proteins were quantified. Effects of propofol on microsomal pentoxyresorufin O-dealkelase (PROD) and ethoxycoumarin O-deethylase (ECOD) activities were determined. KEY FINDINGS: Administration of propofol to CLP-treated rats significantly attenuated sepsis-induced insults. CLP caused augmented serum aspartate aminotransferase and alanine aminotransferase activities and concurrently triggered liver damage. In contrast, treatment with propofol protected against CLP-induced liver dysfunction. As to the mechanisms, the CLP-induced increases in oxidative stress and lipid peroxidation levels and TNF-α and IL-1ß mRNA and protein expressions were subsequently attenuated by propofol. Furthermore, administration of CLP-treated rats with propofol augmented levels of IL-4 in the liver. Phenobarbital treatment of liver microsomes in CLP-treated rats produced less amplification of PROD and ECOD activities, and a smaller amount of 4-hydroxypropofol was metabolized from propofol by liver microsomes. In contrast, more drug interactions occurred with propofol, which decreased PROD and ECOD activities in liver microsomes of CLP-treated rats. SIGNIFICANCE: Taken together, the present study showed that propofol can protect against sepsis-induced liver dysfunction through suppressing hepatic oxidative stress, lipid peroxidation, inflammation, and drug biotransformation and interactions in the liver.

Traumatic osteoarthritis-induced persistent mechanical hyperalgesia in a rat model of anterior cruciate ligament transection plus a medial meniscectomy.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage degeneration, subchondral bone changes, osteophyte formation, and synovitis. A major symptom is pain that is triggered by peripheral and central changes within the pain pathways. Some surgery-induced joint instability rat models of OA were described to mimic traumatic OA. Several behavioral tests were developed to access OA-induced pain. However, follow-up in most studies usually only occurred for about 4 weeks. Since traumatic OA is a chronic disease which gradually develops after trauma, the pattern of pain might differ between early and late stages after the trauma. PURPOSE: To observe the time-dependent development of hypersensitivity after traumatic OA and to determine the best timing and methods to investigate traumatic OA-induced pain. METHODS: Anterior cruciate ligament transection plus medial meniscectomy was used to induce traumatic OA in Sprague-Dawley rats. Traumatic OA-induced pain was evaluated using four different behavioral tests for 15 weeks. RESULTS: A significant difference in mechanical hypersensitivity developed throughout the observational period. It was worst in the first 3 weeks after the operation, then became less significant after 5 weeks but persisted. There were no differences in thermal hyperalgesia or motor coordination. CONCLUSION: Traumatic OA induced mechanical hyperalgesia but did not cause thermal hyperalgesia or influence motor coordination. Furthermore, to investigate chronic pain induced by OA, the observational period should be at least 5 weeks after the intervention. These findings may help in further research and improve our understanding of traumatic OA-induced pain mechanisms.

Liver nitrosation and inflammation in septic rats were suppressed by propofol via downregulating TLR4/NF-κB-mediated iNOS and IL-6 gene expressions.

AIMS: Propofol can be applied as an anesthetic or sedative agent for septic patients. Our previous studies showed that propofol ameliorated inflammation- and nitrosative stress-induced cellular insults. This study further evaluated effects of propofol on cecal ligation and puncture (CLP)-induced septic insults to rats and its possible mechanisms. MAIN METHODS: Wistar rats were administered with CLP and effects of propofol on CLP-induced liver dysfunction and rat death were evaluated. Levels of hepatic or systemic nitrogen oxides (NOx) and interleukin (IL)-6 were quantified. Sequentially, inducible nitric oxide synthase (iNOS) and IL-6 gene expressions, toll-like receptor 4 (TLR4) protein levels, and nuclear factor (NF)-κB translocation were determined. KEY FINDINGS: Subjecting rats to CLP led to body weight loss, liver weight gain, and death. Administration of propofol lessened CLP-induced augmentations of serum and hepatic nitrosative stress and IL-6 levels. Additionally, propofol suppressed CLP-induced enhancements in levels of hepatic iNOS protein. Furthermore, the CLP-induced iNOS and IL-6 mRNA expressions in the liver were inhibited following propofol administration. Sequentially, subjecting rats to CLP enhanced hepatic TLR4 protein levels and NF-κB translocation to nuclei, but propofol inhibited these augmentations. SIGNIFICANCE: Consequently, exposure to propofol protected against CLP-induced liver dysfunction and increased the survival rates of the animals. This study shows that propofol can protect rats against septic insults through suppression of systemic and hepatic nitrosative and inflammatory stress due to inhibition of TLR4/NF-κB-mediated iNOS and IL-6 mRNA and protein expressions.

Transversus Abdominis Plane Block: An Updated Review of Anatomy and Techniques.

PURPOSE OF REVIEW: Transversus abdominis plane (TAP) block is a regional technique for analgesia of the anterolateral abdominal wall. This review highlights the nomenclature system and recent advances in TAP block techniques and proposes directions for future research. RECENT FINDINGS: Ultrasound guidance is now considered the gold standard in TAP blocks. It is easy to acquire ultrasound images; it can be used in many surgeries involving the anterolateral abdominal wall. However, the efficacy of ultrasound-guided TAP blocks is not consistent, which might be due to the use of different approaches. The choice of technique influences the involved area and block duration. To investigate the actual analgesic effects of TAP blocks, we unified the nomenclature system and clarified the definition of each technique. Although a single-shot TAP block is limited in duration, it is still the candidate of the analgesic standard for abdominal wall surgery because the use of the catheter technique and liposomal bupivacaine may overcome this limitation. SUMMARY: Ultrasound-guided TAP blocks are commonly used. With the unified nomenclature and the development of catheter technique and/or liposomal local anesthetics, TAP blocks can be applied more appropriately to achieve better pain control.

Protection of Dexmedetomidine Against Ischemia/Reperfusion-Induced Apoptotic Insults to Neuronal Cells Occurs Via an Intrinsic Mitochondria-Dependent Pathway.

Dexmedetomidine, an agonist of alpha2-adrenergic receptors, is used for critically ill patients to induce and maintain sedation and analgesia. Brain ischemia/reperfusion (I/R) usually causes severe neuronal injuries to intensive care unit patients. This study was aimed to evaluate the effects of dexmedetomidine on I/R-induced insults to neuronal cells and the possible mechanisms. Treatment of neuro-2a cells with dexmedetomidine did not affect cell viability but could protect against I/R-induced cell death. Separately, the I/R-triggered cell shrinkage, DNA fragmentation, and apoptosis in neuro-2a cells were alleviated by dexmedetomidine. As to the mechanisms, exposure of neuro-2a cells to dexmedetomidine substantially attenuated I/R-induced translocation of Bax protein from the cytosol to mitochondria and reduction in the mitochondrial membrane potential (MMP). Successively, dexmedetomidine decreased cytochrome c release from mitochondria to the cytoplasm and consequent cascade activations of caspases-9, -3, and -6 in I/R-treated neuro-2a cells. Interestingly, downregulating caspase-6 activity synergistically improved dexmedetomidine-induced defense against I/R-induced apoptosis of neuro-2a cells. The dexmedetomidine-involved neuroprotection was further confirmed in the other NB41A3 neuronal cells by significantly attenuating I/R-induced changes in the MMP, caspase-3 activation, DNA fragmentation, and cell apoptosis. Taken together, this study has shown the neuroprotective effects of dexmedetomidine against I/R-induced apoptotic insults via an intrinsic Bax-mitochondria-cytochrome c-caspase protease pathway. J. Cell. Biochem. 118: 2635-2644, 2017. © 2016 Wiley Periodicals, Inc.

Effect of Intracuff Lidocaine on Postoperative Sore Throat and the Emergence Phenomenon: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Postoperative sore throat and other airway morbidities are common and troublesome after endotracheal tube intubation general anesthesia (ETGA). We propose lidocaine as endotracheal tube (ETT) cuff inflation media to reduce the postintubation-related emergence phenomenon. METHODS: We searched PubMed, EMBASE, and Cochrane databases systematically for randomized controlled trials (RCTs) that have investigated the outcome of intracuff lidocaine versus air or saline in patients receiving ETGA. Using a random-effects model, we conducted a meta-analysis to assess the relative risks (RRs) and mean difference (MD) of the incidence and intensity of relevant adverse outcomes. RESULTS: We reviewed nineteen trials, which comprised 1566 patients. The incidence of early- and late-phase postoperative sore throat (POST), coughing, agitation, hoarseness, and dysphonia decreased significantly in lidocaine groups, with RRs of 0.46 (95% confidence interval [CI]: 0.31 to 0.68), 0.41 (95% CI: 0.25 to 0.66), 0.43 (95% CI: 0.31 to 0.62), 0.37 (95% CI: 0.25 to 0.55), 0.43 (95% CI: 0.29 to 0.63), and 0.19 (95% CI: 0.08 to 0.5), respectively, when compared with the control groups. The severity of POST also reduced significantly (mean difference [MD] -16.43 mm, 95% CI: -21.48 to -11.38) at 1 h and (MD -10.22 mm, 95% CI: -13.5 to -6.94) at 24 h. Both alkalinized and non-alkalinized lidocaine in the subgroup analyses showed significant benefits in emergence phenomena prevention compared with the control. CONCLUSION: Our results indicate that both alkalinized and non-alkalinized intracuff lidocaine may prevent and alleviate POST and postintubation-related emergence phenomena.

Propofol versus midazolam for upper gastrointestinal endoscopy in cirrhotic patients: a meta-analysis of randomized controlled trials.

BACKGROUND: Sedation during gastrointestinal endoscopy is often achieved using propofol or midazolam in general population. However, impaired protein synthesis, altered drug metabolism, and compromised hepatic blood flow in patients with liver cirrhosis might affect the pharmacokinetics of sedatives, placing cirrhotic patients undergoing endoscopy at a greater risk of adverse events. The objective of this study was to assess comparative efficacies and safety of propofol and midazolam in cirrhotic patients undergoing endoscopy. METHODS: Randomized, controlled trials comparing propofol with midazolam in cirrhotic patients undergoing gastrointestinal endoscopy were selected. We performed the meta-analysis, using a random-effect model, the Review Manager, Version 5.2, statistical software package (Cochrane Collaboration, Oxford, UK) according to the PRISMA guidelines. RESULTS: Five studies between 2003 and 2012, including 433 patients, were included. Propofol provided a shorter time to sedation (weight mean difference: -2.76 min, 95% confidence interval: -3.00 to -2.51) and a shorter recovery time (weight mean difference -6.17 min, 95% confidence interval: -6.81 to -5.54) than midazolam did. No intergroup difference in the incidence of hypotension, bradycardia, or hypoxemia was observed. Midazolam was associated with the deterioration of psychometric scores for a longer period than propofol. CONCLUSION: This meta-analysis suggests that Propofol sedation for endoscopy provides more rapid sedation and recovery than midazolam does. The risk of sedation-related side effects for propofol does not differ significantly from that of midazolam. The efficacy of propofol in cirrhotic patients undergoing endoscopy is superior to those of midazolam.

Comparative proteomic analysis of rat left ventricle in a subtotal nephrectomy model.

BACKGROUND: Chronic kidney disease (CKD) is associated with cardiac hypertrophy that leads to increased cardiovascular morbidity and mortality. To date, use of the renin-angiotensin-aldosterone system blockade has been the main treatment modality. However, renin-angiotensin-aldosterone system blockade by the angiotensin converting enzyme inhibitors (ACEi) can only partially reverse the cardiac hypertrophy without having a significant impact on all-cause mortality as evidenced by meta-analyses from clinical trials. It is imperative to elucidate the molecular pathogenesis of CKD-related cardiomyopathy for potential targets in further treatment. METHODS: Male Sprague-Dawley rats that underwent subtotal nephrectomy (SNX) rats were established as the CKD model. A hemodynamic study was used to evaluate the left ventricle (LV) structural and functional alterations. We used proteomic techniques to profile the LV protein changes among sham-operated rats, SNX rats, and SNX rats with 6 months of ACEi enalapril interventions. The differentially expressed proteins were further annotated by functional and network analyses. RESULTS: As compared to the sham-operated rats, the SNX rats had 25 upregulated and 46 decreased protein expression. The top canonical pathways identified by ingenuity pathway analysis for the CKD cardiomyopathy were mitochondrial dysfunction, oxidative phosphorylation, fatty acid ß oxidation, protein ubiquitination, and ketolysis. The most relevant functions extracted from these networks contained 27 and 23 focused proteins, respectively. They were related to cellular assembly and organization, RNA posttranscriptional modification, and protein synthesis. After ACEi intervention for 6 weeks, the residual canonical pathways identified by ingenuity pathway analysis that mediated the CKD-related cardiomyopathy were mitochondrial dysfunction, ketolysis, phenylalanine degradation IV, and putrescine degradation III. There were decreased Sirt3 and SNRNP, and increased monoamine oxidase and SAHH expression in the LV of SNX rats that could not be reversed by the ACEi. CONCLUSION: Our studies provide a repertoire of potential biomarkers related to cardiac hypertrophy in CKD. There are still residual disturbed molecules/pathways despite ACEi intervention. Further studies are warranted to investigate these potential novel targets to alleviate CKD-related cardiomyopathy.

How comorbidities and preoperative expenditures correlate with postoperative adverse outcomes.

OBJECTIVES: To examine the correlation of preexisting illnesses and preoperative medical expenditures with postoperative major adverse outcomes among geriatric surgical patients. STUDY DESIGN: Retrospective cohort study using claims from Taiwan's National Health Insurance Research Database. METHODS: All geriatric patients aged >65 years receiving inpatient surgeries during 2004 to 2007 under universal healthcare coverage were included. Surgical patients aged 55 to 64 years were the reference group. Risk-adjusted 30-day postoperative complication and mortality rates among elderly patients in various age sectors were analyzed and correlated with the preexisting illnesses and preoperative medical expenditures quantitatively. RESULTS: Among 432,614 elderly surgical patients in specific age sectors and 238,802 controls, the prevalence of preexisting illnesses and the risk-adjusted postoperative adverse outcome rates were highly age dependent and illness related. When comparing patients aged >85 years with patients aged 55 to 64 years, the adjusted odds ratios were 2.74 (95% confidence interval [CI], 2.67-2.82) and 3.56 (95% CI 3.31-3.84) for incidence of major postoperative complications and mortality after major complications, respectively. Numbers of preexisting illnesses increased in an age-dependent pattern and the preoperative 24-month medical expenditures increased incrementally with the numbers of comorbidities. Postoperative major complications, but not mortality rates, were highly correlated with the numbers of comorbidities and increased parallel with preoperative 24-month comorbidity-related medical expenditures, especially in the younger age group. CONCLUSIONS: Adjusting for preexisting covariates, geriatric patients had an age-dependent, illness-related, and expenditure-associated pattern of higher postoperative complication and mortality rates. The numbers of comorbidities and preoperative medical expenditures had high predictive value for postoperative adverse outcomes.

Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK.

Death-associated protein kinase (DAPK) is a death domain-containing serine/threonine kinase, and participates in various apoptotic paradigms. Here, we identify the extracellular signal-regulated kinase (ERK) as a DAPK-interacting protein. DAPK interacts with ERK through a docking sequence within its death domain and is a substrate of ERK. Phosphorylation of DAPK at Ser 735 by ERK increases the catalytic activity of DAPK both in vitro and in vivo. Conversely, DAPK promotes the cytoplasmic retention of ERK, thereby inhibiting ERK signaling in the nucleus. This reciprocal regulation between DAPK and ERK constitutes a positive feedback loop that ultimately promotes the apoptotic activity of DAPK. In a physiological apoptosis system where ERK-DAPK interplay is reinforced, downregulation of either ERK or DAPK suppresses such apoptosis. These results indicate that bidirectional signalings between DAPK and ERK may contribute to the apoptosis-promoting function of the death domain of DAPK.