Perioperative Risk Factors for Persistent Postsurgical Pain After Inguinal Hernia Repair: Systematic Review and Meta-Analysis.

Persistent postsurgical pain (PPSP) is one of the most bothersome and disabling long-term complications after inguinal hernia repair surgery. Understanding perioperative risk factors that contribute to PPSP can help identify high-risk patients and develop risk-mitigation approaches. The objective of this study was to systematically review and meta-analyze risk factors that contribute to PPSP after inguinal hernia repair. The literature search resulted in 303 papers included in this review, 140 of which were used for meta-analyses. Our results suggest that younger age, female sex, preoperative pain, recurrent hernia, postoperative complications, and postoperative pain are associated with a higher risk of PPSP. Laparoscopic techniques reduce the PPSP occurrence compared to anterior techniques such as Lichtenstein repair, and tissue-suture techniques such as Shouldice repair. The use of fibrin glue for mesh fixation was consistently associated with lower PPSP rates compared to tacks, staples, and sutures. Considerable variability was observed with PPSP assessment and reporting methodology in terms of study design, follow-up timing, clarity of pain definition, as well as pain intensity or interference threshold. High or moderate risk of bias in at least one domain was noted in >75% of studies. These may limit the generalizability of our results. Future studies should assess and report comprehensive preoperative and perioperative risk factors for PPSP adjusted for confounding factors, and develop risk-prediction models to drive stratified PPSP-mitigation trials and personalized clinical decision-making. PERSPECTIVE: This systematic review and meta-analysis summarizes the current evidence on risk factors for persistent pain after inguinal hernia repair. The findings can help identify patients at risk and test personalized risk-mitigation approaches to prevent pain. PROSPERO REGISTRATION: htttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=154663.

Feasibility of combining spatial computing and AI for mental health support in anxiety and depression.

The increasing need for mental health support and a shortage of therapists have led to the development of the eXtended-reality Artificial Intelligence Assistant (XAIA). This platform combines spatial computing, virtual reality (VR), and artificial intelligence (AI) to provide immersive mental health support. Utilizing GPT-4 for AI-driven therapy, XAIA engaged participants with mild-to-moderate anxiety or depression in biophilic VR environments. Speaking with an AI therapy avatar in VR was considered acceptable, helpful, and safe, with participants observed to engage genuinely with the program. However, some still favored human interaction and identified shortcomings with using a digital VR therapist. The study provides initial evidence of the acceptability and safety of AI psychotherapy via spatial computing, warranting further research on technical enhancements and clinical impact.

Bacterial TLR2/6 Ligands Block Ciliogenesis, Derepress Hedgehog Signaling, and Expand the Neocortex.

Microbial components have a range of direct effects on the fetal brain. However, little is known about the cellular targets and molecular mechanisms that mediate these effects. Neural progenitor cells (NPCs) control the size and architecture of the brain and understanding the mechanisms regulating NPCs is crucial to understanding brain developmental disorders. We identify ventricular radial glia (vRG), the primary NPC, as the target of bacterial cell wall (BCW) generated during the antibiotic treatment of maternal pneumonia. BCW enhanced proliferative potential of vRGs by shortening the cell cycle and increasing self-renewal. Expanded vRGs propagated to increase neuronal output in all cortical layers. Remarkably, Toll-like receptor 2 (TLR2), which recognizes BCW, localized at the base of primary cilia in vRGs and the BCW-TLR2 interaction suppressed ciliogenesis leading to derepression of Hedgehog (HH) signaling and expansion of vRGs. We also show that TLR6 is an essential partner of TLR2 in this process. Surprisingly, TLR6 alone was required to set the number of cortical neurons under healthy conditions. These findings suggest that an endogenous signal from TLRs suppresses cortical expansion during normal development of the neocortex and that BCW antagonizes that signal through the TLR2/cilia/HH signaling axis changing brain structure and function. IMPORTANCE Fetal brain development in early gestation can be impacted by transplacental infection, altered metabolites from the maternal microbiome, or maternal immune activation. It is less well understood how maternal microbial subcomponents that cross the placenta, such as bacterial cell wall (BCW), directly interact with fetal neural progenitors and neurons and affect development. This scenario plays out in the clinic when BCW debris released during antibiotic therapy of maternal infection traffics to the fetal brain. This study identifies the direct interaction of BCW with TLR2/6 present on the primary cilium, the signaling hub on fetal neural progenitor cells (NPCs). NPCs control the size and architecture of the brain and understanding the mechanisms regulating NPCs is crucial to understanding brain developmental disorders. Within a window of vulnerability before the appearance of fetal immune cells, the BCW-TLR2/6 interaction results in the inhibition of ciliogenesis, derepression of Sonic Hedgehog signaling, excess proliferation of neural progenitors, and abnormal cortical architecture. In the first example of TLR signaling linked to Sonic Hedgehog, BCW/TLR2/6 appears to act during fetal brain morphogenesis to play a role in setting the total cell number in the neocortex.

Timing of percutaneous endoscopic gastrostomy tube placement in post-stroke patients does not impact mortality, complications, or outcomes.

BACKGROUND: Percutaneous Endoscopic Gastrostomy (PEG) tubes are often placed for dysphagia following a stroke in order to maintain sufficient caloric intake. The 2011 ASGE guidelines recommend delaying PEG tube placement for two weeks, as half of patients with dysphagia improve within 2 wk. There are few studies comparing outcomes based on timing of PEG tube placement, and there is increasing demand for early PEG tube placement to meet requirements for timely discharge to rehab and skilled nursing facilities. AIM: To assess the safety of early (≤ 7 d post stroke) vs late (> 7 d post stroke) PEG tube placement and evaluate whether pre-procedural risk factors could predict mortality or complications. METHODS: We performed a retrospective study of patients undergoing PEG tube placement for dysphagia following a stroke at two hospitals in Saint Louis, MO between January 2011 and December 2017. Patients were identified by keyword search of endoscopy reports. Mortality, peri-procedural complication rates, and post-procedural complication rates were compared in both groups. Predictors of morbidity and mortality such as protein-calorie malnutrition, presence of an independent cardiovascular risk equivalent, and presence of Systemic inflammatory response syndrome (SIRS) criteria or documented infection were evaluated by multivariate logistic regression. RESULTS: 154 patients had a PEG tube placed for dysphagia following a stroke, 92 in the late group and 62 in the early group. There were 32 observed deaths, with 8 occurring within 30 d of the procedure. There was an increase in peri-procedural and post-procedural complications with delayed PEG placement which was not statistically significant. Hospital length of stay was significantly less in patients with early PEG tube placement (12.9 vs 22.34 d, P < 0.001). Protein calorie malnutrition, presence of SIRS criteria and/or documented infection prior to procedure or having a cardiovascular disease risk equivalent did not significantly predict mortality or complications. CONCLUSION: Early PEG tube placement following a stroke did not result in a higher rate of mortality or complications and significantly decreased hospital length of stay. Given similar safety outcomes in both groups, early PEG tube placement should be considered in the appropriate patient to potentially reduce length of hospital stay and incurred costs.

Methadone pharmacogenetics in vitro and in vivo: Metabolism by CYP2B6 polymorphic variants and genetic variability in paediatric disposition.

AIMS: Methadone metabolism and clearance are determined principally by polymorphic cytochrome P4502B6 (CYP2B6). Some CYP2B6 allelic variants affect methadone metabolism in vitro and disposition in vivo. We assessed methadone metabolism by CYP2B6 minor variants in vitro. We also assessed the influence of CYP2B6 variants, and P450 oxidoreductase (POR) and CYP2C19 variants, on methadone clearance in surgical patients in vivo. METHODS: CYP2B6 and P450 oxidoreductase variants were coexpressed with cytochrome b5 . The metabolism of methadone racemate and enantiomers was measured at therapeutic concentrations and intrinsic clearances were determined. Adolescents receiving methadone for surgery were genotyped for CYP2B6, CYP2C19 and POR, and methadone clearance and metabolite formation clearance were determined. RESULTS: In vitro, CYP2B6.4 was more active than wild-type CYP2B6.1. CYPs 2B6.5, 2B6.6, 2B6.7, 2B6.9, 2B6.17, 2B6.19 and 2B6.26 were less active. CYPs 2B6.16 and 2B6.18 were inactive. CYP2B6.1 expressed with POR variants POR.28, POR.5 and P228L had lower rates of methadone metabolism than wild-type reductase. In vivo, methadone clinical clearance decreased linearly with the number of CYP2B6 slow metabolizer alleles, but was not different in CYP2C19 slow or rapid metabolizer phenotypes, or in carriers of the POR*28 allele. CONCLUSIONS: Several CYP2B6 and POR variants were slow metabolizers of methadone in vitro. Polymorphisms in CYP2B6, but not CYP2C19 or P450 reductase, affected methadone clearance in vivo. CYP2B6 polymorphisms 516G>T and 983T>C code for canonical loss of function variants and should be assessed when considering genetic influences on clinical methadone disposition. These complementary translational in vitro and in vivo results inform on pharmacogenetic variability affecting methadone disposition in patients.

Primary jejunal amelanotic melanoma: case report and review of literature.

Intussusception more commonly occurs in pediatrics but is a rare cause of bowel obstruction and gastrointestinal bleeding in adults. It typically occurs in adults due to a malignancy, which serves as a pathologic lead point. We present a case of a 64-year-old female with nausea, vomiting, and melena who was found to have intussusception associated with a primary jejunal amelanotic melanoma. Both intussusception and primary small bowel melanomas are rare causes of obstruction and bleeding. Intussusception occurring as a result of a primary small bowel amelanotic melanoma is exceedingly rare with very few reported cases. We provide a case report and review of the literature.

Grisel's syndrome: a case report on this rare pediatric disease and its anesthetic challenges.

BACKGROUND: Grisel's syndrome is a non-traumatic atlantoaxial subluxation associated with inflammatory conditions of the head and neck, which occurs primarily in children. Increased flexibility of the ligaments during inflammation is implicated in the pathogenesis of the subluxation between the axis and atlas. The potential sequelae may be severe, and early diagnosis and treatment of Grisel's syndrome can prevent tragic outcomes. CASE PRESENTATION: We present a case of torticollis in an 8-year-old child. She had a two-week history of a streptococcal throat infection. The patient was treated with several different methods of conservative care, including muscle relaxation, cervical halter traction, and Halo application. However, the torticollis persisted. The patient then required surgical correction involving cervical spine fusion. She had no complications and experienced no reoccurrence of the torticollis to date. CONCLUSION: Grisel's syndrome is a pathology for which conservative management is successful in most cases. Cases requiring surgical intervention are rarely documented in the literature. Our case is significant, as in spite of aggressive conservative management, the patient required surgical correction. Patients requiring surgical management of Grisel's syndrome may require additional anesthetic exposure for diagnostic interventions like magnetic resonance imaging or neck manipulations for closed reduction. We discuss the features of Grisel's syndrome and specific anesthetic management considerations for procedures such as magnetic resonance imaging, application of cervical traction, and surgical correction of torticollis.

Description and function of a difficult airway service.

The goal of the Pediatric Difficult Airway Service (DAS) is to improve the care of children with airway abnormalities primarily through identification of children at risk for failed airway management. The airway service encourages early recognition and provides consultation, a plan for airway management, expertise in airway management, and follow-up care for children who have a difficult airway. The service has improved the education of healthcare professionals and heightened awareness about the consequences of failed airway management.

Sequence of same-day upper and lower gastrointestinal endoscopy does not affect total procedure' time or medication use: A randomized trial.

BACKGROUND AND AIM: Same-day double upper and lower gastrointestinal endoscopy is frequently performed due to overlapping indications. However, it is unclear whether an upper-lower (U-L) or lower-upper (L-U) sequence is optimal. We analyzed the effect of sequence on total procedure time and sedation use. METHODS: A total of 100 patients scheduled for same-day double endoscopy were randomized to the U-L or L-U sequence arm. Primary outcomes, mean total procedure time, and sedative dosages were compared using a t-test. We also explored associations of the primary outcomes with patient-related and procedure-related factors. RESULTS: Comparing U-L and L-U sequences, mean total procedure time was 41.9 (16.2) versus 43.0 (14.5) min (P = 0.73), diphenhydramine dose 5.5 (15.4) versus 4.5 (14.0) mg (P = 0.74), fentanyl dose 71.5 (119.3) versus 77.6 (164.02) µg (P = 0.83), midazolam dose 1.6 (2.5) versus 1.4 (2.7) mg (P = 0.69), and propofol dose 437.4 (351.4) versus 444.5 (256.0) mg (P = 0.91), respectively. Total procedure and upper endoscopy times were significantly longer with trainee presence (P = 0.0002) and shorter with conscious sedation (P = 0.003). Upper endoscopy time was longer with higher body mass index (P = 0.001), and lower endoscopy time was longer in patients with cirrhosis or chronic kidney disease (P = 0.002 and 0.009, respectively). Time between procedures was significantly longer in the L-U sequence (7.4 [2.9] vs 5.3 [1.1] min, [P < 0.001]). The study had 80% power to detect an 8 min difference in total procedure time. CONCLUSIONS: The sequence of same-day double gastrointestinal endoscopy does not affect total procedure time or medication use. Longer total procedure and upper endoscopy times were associated with trainee presence and use of conscious sedation.

Formation of Pancreatoduodenal Fistula in Intraductal Papillary Mucinous Neoplasm of the Pancreas Decreased the Frequency of Recurrent Pancreatitis.

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are characterized by proliferation of mucin-secreting cells in the main pancreatic duct (PD) or its branches. The secreted thick mucin usually leads to PD obstruction and dilation. A common complication of IPMN is recurrent acute pancreatitis secondary to poor pancreatic fluid drainage, and rarely, pancreatobiliary and pancreatointestinal fistulae. We describe a unique case of IPMN in a 57-year-old male who was referred to our institution for evaluation of recurrent acute pancreatitis. After extensive evaluation, he was diagnosed with main duct IPMN. Intraductal PD biopsy revealed intestinal type IPMN with intermediate grade dysplasia. Patient was managed clinically by large caliber (10 French) PD stenting which eliminated his recurrent acute pancreatitis. The patient was initially referred for pancreatic resection; however, surgery was aborted and evaluated to be high risk with high morbidity secondary to the extensive adhesions between the pancreas and surrounding structures. Patient remained clinically stable for a few years except for an episode of acute pancreatitis that happened after a trial of stent removal. Subsequently, the patient did well after the PD stent was replaced. Recently, repeat abdominal imaging revealed a large pancreatoduodenal fistula which was confirmed on repeat endoscopic retrograde cholangiopancreatography. We were able to perform pancreatoscopy by advancing a regular upper scope through the fistula and into the PD. Interestingly, the fistula relieved the symptoms of obstruction and subsequently decreased the frequency of recurrent pancreatitis episodes with no further episodes at 6 months follow-up. This case highlights the importance of providing adequate PD drainage to reduce the frequency of recurrent acute pancreatitis in the setting of main duct IPMN, especially if the patient is not a surgical candidate. Also, physicians need to monitor for complications such as fistula formation between the pancreas and surrounding structures in the setting of chronic inflammation due to recurrent episodes of pancreatitis. Early identification of a fistula is important for surgical planning. Furthermore, since recent studies suggested a higher incidence of additional primary malignancies in patients with IPMN of the pancreas compared to the general population, patients may be considered for screening for other primary malignancies.

Peptic Ulcer Disease and Helicobacter pylori infection.

Peptic ulcer disease (PUD) is a common condition that both primary care providers and gastroenterologists encounter. Symptoms of peptic ulcer disease are variable and may include abdominal pain, nausea, vomiting, weight loss and bleeding or perforation with complicated disease. Identifying the risk factors and mechanisms that lead to the development of PUD helps to understand the approach behind diagnostic and treatment strategies.

Tertiary Care Referrals for Fractures in Children.

PURPOSE: With limited local access to pediatric subspecialty care outside major metropolitan areas, tertiary care hospitals treat many children originally seen at outside facilities for relatively brief but urgent surgical procedures. This referral-based care imposes significant financial and psychological stress on the families. DESIGN: Prospective, survey methodology was used. METHODS: Families of children aged 0-18 years admitted to the St. Louis Children's Hospital for surgical repair of fractures were surveyed. The questionnaire was developed by the research team and measured a variety of fields. FINDINGS: The operative procedure in the majority of these children was relatively brief in both groups, often less than one hour. The time of injury to their discharge from our hospital, however, extended to 36 hours. Families missed several days of work. Many children were kept NPO longer than needed. CONCLUSIONS: Our preliminary evaluation suggests that a relatively minor unexpected surgery of a child can impose significant financial, organizational, and psychological burden on the family.

Neurobiology of Propofol Addiction and Supportive Evidence: What Is the New Development?

Propofol is a short-acting intravenous anesthetic agent suitable for induction and maintenance of general anesthesia as well as for procedural and intensive care unit sedation. As such it has become an unparalleled anesthetic agent of choice in many institutional and office practices. However, in addition to its idealistic properties as an anesthetic agent, there is accumulating evidence suggesting its potential for abuse. Clinical and experimental evidence has revealed that not only does propofol have the potential to be abused, but also that addiction to propofol shows a high mortality rate. Based on this evidence, different researchers have shown interest in determining the probability of propofol to be an addictive agent by comparing it with other drugs of abuse and depicting a functional similitude that involves the mesocorticolimbic pathway of addiction. In light of this, the Drug Enforcement Agency and the American Society of Anesthesiologists have put forth certain safety recommendations for the use of propofol. Despite this, the abuse potential of propofol has been challenged at different levels and therefore the preeminent focus will be to further validate the linkage from medicinal and occasional use of propofol to its addiction, as well as to explore the cellular and molecular targets involved in establishing this linkage, so as to curb the harm arising out of it. This review incorporates the clinical and biomolecular evidence supporting the abuse potential of propofol and brings forth the promising targets and the foreseeable mechanism causing the propofol addiction phenotypes, which can be called upon for future developments in this field.

Risk of Gastric Cancer Among Patients With Intestinal Metaplasia of the Stomach in a US Integrated Health Care System.

BACKGROUND & AIMS: Gastric intestinal metaplasia (GIM) is a common finding from routine endoscopies. Although GIM is an early step in gastric carcinogenesis, there is controversy regarding routine surveillance of patients with GIM in regions with a low prevalence of gastric cancer. We aimed to determine the incidence of gastric cancer among patients with GIM and risk factors for gastric cancer. METHODS: We performed a retrospective cohort study of patients from the Kaiser Permanente Southern California region diagnosed with GIM from 2000 through 2011. GIM was identified by a keyword search of pathology reports; gastric cancer cases were identified by cross-reference with an internal cancer registry. The incidence of gastric cancer in patients with GIM (n = 923; median age at diagnosis, 68 y) was compared with that of an age- and sex-matched reference population (controls). Risk factors such as ethnicity, smoking status, history of Helicobacter pylori infection, and family history of gastric cancer were evaluated by individual Cox proportional hazards regression. We then performed a second case-cohort study to evaluate the risk of gastric cancer based on the location and extent of GIM. The median duration of follow-up evaluation was 4.6 years (interquartile range, 3.0-6.7 y). RESULTS: We identified 25 patients with GIM who developed gastric cancers. Seventeen cases of cancer were diagnosed at the same time as the diagnosis of GIM. Eight cases of cancer were identified within a median time period of 4.6 years after a diagnosis of GIM (interquartile range, 2-5.7 y). The overall incidence rate for the cohort was 1.72 (95% confidence interval, 0.74-3.39). Among the risk factors evaluated, only family history (hazard ratio, 3.8; 95% confidence interval, 1.5-9.7; P = .012) and extent of GIM (odds ratio, 9.4; 95% confidence interval, 1.8-50.4) increased the risk for gastric cancer. The incidence rate for gastric cancer in patients with a positive family history was 8.12 (95% confidence interval, 1.67-23.73). CONCLUSIONS: In an analysis of patients with GIM listed in the Kaiser Permanente Southern California database, 2.7% were diagnosed with gastric cancer; almost 70% of cases of gastric cancer were detected at the time of GIM diagnosis. Family history and extensive metaplasia were associated with an increased risk of subsequent gastric cancer. Targeted surveillance of patients with these criteria could increase early detection of gastric cancer.

Simulation-Based Assessment of ECMO Clinical Specialists.

OBJECTIVE: The aims of the study were (1) to create multiple scenarios that simulate a range of urgent and emergent extracorporeal membrane oxygenation (ECMO) events and (2) to determine whether these scenarios can provide reliable and valid measures of a specialist's advanced skill in managing ECMO emergencies. DESIGN: Multiscenario simulation-based performance assessment was performed. SETTING: The study was conducted in the Saigh Pediatric Simulation Center at St. Louis Children's Hospital. SUBJECTS: ECMO clinical specialists participated in the study. MEASUREMENTS AND MAIN RESULTS: Twenty-five ECMO specialists completed 8 scenarios presenting acute events in simulated ECMO patients. Participants were evaluated by 2 separate reviewers for completion of key actions and for global performance. The scores were highest for the hemodilution scenario, whereas the air entrainment scenario had the lowest scores. Psychometric analysis demonstrated that ECMO specialists with more than 1 year of experience outperformed the specialists with less than 1 year of experience. Participants endorsed these sessions as important and representative of events that might be encountered in practice. CONCLUSIONS: The scenarios could serve as a component of an ECMO education curriculum and be used to assess clinical specialists' readiness to manage ECMO emergencies.

Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency.

Attenuated auto-lysosomal system has been associated with Alzheimer disease (AD), yet all underlying molecular mechanisms leading to this impairment are unknown. We show that the amino acid sensing of mechanistic target of rapamycin complex 1 (mTORC1) is dysregulated in cells deficient in presenilin, a protein associated with AD. In these cells, mTORC1 is constitutively tethered to lysosomal membranes, unresponsive to starvation, and inhibitory to TFEB-mediated clearance due to a reduction in Sestrin2 expression. Normalization of Sestrin2 levels through overexpression or elevation of nuclear calcium rescued mTORC1 tethering and initiated clearance. While CLEAR network attenuation in vivo results in buildup of amyloid, phospho-Tau, and neurodegeneration, presenilin-knockout fibroblasts and iPSC-derived AD human neurons fail to effectively initiate autophagy. These results propose an altered mechanism for nutrient sensing in presenilin deficiency and underline an importance of clearance pathways in the onset of AD.

Zoster Vaccine and the Risk of Postherpetic Neuralgia in Patients Who Developed Herpes Zoster Despite Having Received the Zoster Vaccine.

BACKGROUND: Although it is evident that zoster vaccination reduces postherpetic neuralgia (PHN) risk by reducing herpes zoster (HZ) occurrence, it is less clear whether the vaccine protects against PHN among patients who develop HZ despite previous vaccination. METHODS: This cohort study included immunocompetent patients with HZ. The vaccinated cohort included 1155 individuals who were vaccinated against HZ at age ≥60 years and had an HZ episode after vaccination. Vaccinated patients were matched 1:1 by sex and age with unvaccinated patients. Trained medical residents reviewed the full medical record to determine the presence of HZ-related pain at 1, 2, 3, and 6 months after HZ diagnosis. The incidence of PHN was compared between vaccinated and unvaccinated -patients. RESULTS: Thirty vaccinated women (4.2%) experienced PHN, compared with 75 unvaccinated women (10.4%), with an adjusted relative risk of 0.41 (95% confidence interval, .26-.64). PHN occurred in 26 vaccinated men (6.0%) versus 25 unvaccinated men (5.8%), with an adjusted relative risk of 1.06 (.58-1.94). These associations did not differ significantly by age. CONCLUSIONS: Among persons experiencing HZ, prior HZ vaccination is associated with a lower risk of PHN in women but not in men. This sex-related difference may reflect differences in healthcare-seeking patterns and deserve further investigation.

Soluble neuregulin-1 has bifunctional, concentration-dependent effects on Schwann cell myelination.

Members of the neuregulin-1 (Nrg1) growth factor family play important roles during Schwann cell development. Recently, it has been shown that the membrane-bound type III isoform is required for Schwann cell myelination. Interestingly, however, Nrg1 type II, a soluble isoform, inhibits the process. The mechanisms underlying these isoform-specific effects are unknown. It is possible that myelination requires juxtacrine Nrg1 signaling provided by the membrane-bound isoform, whereas paracrine stimulation by soluble Nrg1 inhibits the process. To investigate this, we asked whether Nrg1 type III provided in a paracrine manner would promote or inhibit myelination. We found that soluble Nrg1 type III enhanced myelination in Schwann cell-neuron cocultures. It improved myelination of Nrg1 type III(+/-) neurons and induced myelination on normally nonmyelinated sympathetic neurons. However, soluble Nrg1 type III failed to induce myelination on Nrg1 type III(-/-) neurons. To our surprise, low concentrations of Nrg1 type II also elicited a similar promyelinating effect. At high doses, however, both type II and III isoforms inhibited myelination and increased c-Jun expression in a manner dependent on Mek/Erk (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) activation. These results indicate that paracrine Nrg1 signaling provides concentration-dependent bifunctional effects on Schwann cell myelination. Furthermore, our studies suggest that there may be two distinct steps in Schwann cell myelination: an initial phase dependent on juxtacrine Nrg1 signaling and a later phase that can be promoted by paracrine stimulation.