Current clinical evidence is insufficient to support HMME-PDT as the first choice of treatment for young children with port wine birthmarks.

BACKGROUND: Port wine birthmark (PWB) is a congenital vascular malformation of the skin. Pulsed dye laser (PDL) is the "gold standard" for the treatment of PWB globally. Hematoporphyrin monomethyl ether (HMME or hemoporfin)-mediated photodynamic therapy (HMME-PDT) has emerged as the first choice for PWB treatment, particularly for young children, in many major hospitals in China during the past several decades. AIM: To evaluate whether HMME-PDT is superior to PDL by comparing the clinical efficacies of both modalities. METHOD: PubMed records were searched for all relevant studies of PWB treatment using PDL (1988-2023) or HMME-PDT (2007-2023). Patient characteristics and clinical efficacies were extracted. Studies with a quartile percentage clearance or similar scale were included. A mean color clearance index (CI) per study was calculated and compared among groups. An overall CI (C0), with data weighted by cohort size, was used to evaluate the final efficacy for each modality. RESULT: A total of 18 HMME-PDT studies with 3910 patients in China were eligible for inclusion in this analysis. Similarly, 40 PDL studies with 5094 patients from nine different countries were eligible for inclusion in this analysis. Over 58% of patients in the HMME-PDT studies were minors (<18 years old). A significant portion (21.3%) were young children (<3 years old). Similarly, 33.2% of patients in the PDL studies were minors. A small proportion (9.3%) was young children. The overall clearance rates for PDL were slightly, but not significantly, higher than those for HMME-PDT in cohorts with patients of all ages (C0, 0.54 vs. 0.48, p = 0.733), subpopulations with only minors (C0, 0.54 vs. 0.46, p = 0.714), and young children (C0, 0.67 vs. 0.50, p = 0.081). Regrettably, there was a lack of long-term data on follow-up evaluations for efficacy and impact of HMME-PDT on young children in general, and central nervous system development in particular, because their blood-brain barriers have a greater permeability as compared to adults. CONCLUSION: PDL shows overall albeit insignificantly higher clearance rates than HMME-PDT in patients of all ages; particularly statistical significance is nearly achieved in young children. Collectively, current evidence is insufficient to support HMME-PDT as the first choice of treatment of PWBs in young children given: (1) overall inferior efficacy as compared to PDL; (2) risk of off-target exposure to meningeal vasculature during the procedure; (3) administration of steriods for mitigation of side effects; -and (4) lack of long-term data on the potential impact of HMME on central nervous system development in young children.

Brent Technique of Repair Versus Nagata Auricular Reconstruction for Microtia Reconstruction: A Systematic Review and Meta-Analysis.

BACKGROUND: Up to 17.4 in every 10,000 births are affected by microtia, but no consensus exists on a gold standard technique for autogenous repair. In this study, the authors compare 2 common methods-the Brent and Nagata autogenous costal cartilage ear reconstruction techniques. A systematic review of the literature and a quantitative meta-analysis to compare the outcomes of these 2 approaches were performed. The outcomes analyzed included rates of infection, necrosis, cartilage exposure, cartilage resorption, hematoma, wire extrusion, and hypertrophic scar. METHODS: A MEDLINE database systematic review with the following keywords: microtia, Brent, and Nagata was performed. Case reports and articles without original data or patient outcomes were excluded. Inclusion methods for study selection are outlined in Supplemental Digital Content 1, http://links.lww.com/SCS/F461 , below. The prevalence of outcomes for each study was analyzed through meta-analysis of proportions using Stata. RESULTS: A total of 536 potential studies were retrieved for review. Twelve of these studies met inclusion criteria. Four studies utilized the Brent method of repair with the inclusion of 563 ear reconstructions. Nine studies implemented the Nagata technique in 2304 reconstructions. Two studies directly compared the Brent (327 ears) and Nagata (471 ears) techniques. The calculated rate and 95% confidence intervals are summarized in Supplemental Digital Content 2, http://links.lww.com/SCS/F461 . There were no statistically significant differences in complication rates between the Brent and Nagata microtic reconstruction techniques identified in this study. CONCLUSIONS: The Brent and Nagata microtia reconstruction techniques have no difference in the risk of infection, necrosis, cartilage exposure, cartilage resorption, hematoma, wire extrusion, or hypertrophic scars.

Newtonian gravitation in Maxwell spacetime.

This paper argues for the appropriateness of Maxwell spacetime as the minimal spacetime structure in which one may formulate a theory of Newtonian gravity. I begin by presenting an intrinsic characterization of Maxwell gravitation that, eschewing covariant derivative operators, makes use only of a standard of rotation and other more primitive structures. I then revisit the question of whether Maxwell gravitation and Newton-Cartan theory are equivalent, demonstrating that previous results may be extended to all but the vacuum case since candidate geometrizations are not free to vary through purely gravitational degrees of freedom. Lastly, I consider the space of possible geometrizations of Maxwell gravitation more broadly and argue for a sense in which curvature is not entirely a matter of convention in classical spacetimes.

Supporting materials: Endothelial cells differentiated from patient dermal fibroblast-derived induced pluripotent stem cells resemble vascular malformations of Port Wine Birthmark.

Background: Port wine birthmark (PWB) is a congenital vascular malformation resulting from developmentally defective endothelial cells (ECs). Developing clinically relevant disease models for PWB studies is currently an unmet need. Objective: Our study aims to generate PWB-derived induced pluripotent stem cells (iPSCs) and iPSC-derived ECs that preserve disease-related phenotypes. Methods: PWB iPSCs were generated by reprogramming lesional dermal fibroblasts and differentiated into ECs. RNA-seq was performed to identify differentially expressed genes (DEGs) and enriched pathways. The functional phenotypes of iPSC-derived ECs were characterized by capillary-like structure (CLS) formation in vitro and Geltrex plug-in assay in vivo . Results: Human PWB and control iPSC lines were generated through reprogramming of dermal fibroblasts by introducing the "Yamanaka factors" (Oct3/4, Sox2, Klf4, c-Myc) into them; the iPSCs were successfully differentiated into ECs. These iPSCs and their derived ECs were validated by expression of a series of stem cell and EC biomarkers, respectively. PWB iPSC-derived ECs showed impaired CLS in vitro with larger perimeters and thicker branches as compared to control iPSC-derived ECs. In the plug-in assay, perfused human vasculature formed by PWB iPSC- derived ECs showed bigger perimeters and greater densities than those formed by control iPSC- derived ECs in severe combined immune deficient (SCID) mice. The transcriptome analysis showed that dysregulated pathways of stem cell differentiation, Hippo, Wnt, and focal adhesion persisted through differentiation of PWB iPSCs to ECs. Functional enrichment analysis showed that Hippo and Wnt pathway-related PWB DEGs are enriched for vasculature development, tube morphology, endothelium development, and EC differentiation. Further, members of the zinc finger (ZNF) gene family were overrepresented among the DEGs in PWB iPSCs. ZNF DEGs confer significant functions in transcriptional regulation, chromatin remodeling, protein ubiquitination, and retinoic acid receptor signaling. Furthermore, NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways were dysregulated in PWB ECs as readouts of impaired differentiation. Conclusions: PWB iPSC-derived ECs render a novel and clinically-relevant disease model by retaining pathological phenotypes. Our data demonstrate multiple pathways, such as Hippo and Wnt, NF-kappa B, TNF, MAPK, and cholesterol metabolism, are dysregulated, which may contribute to the development of differentiation-defective ECs in PWB. Bulleted statements: What is already known about this topic?: Port Wine Birthmark (PWB) is a congenital vascular malformation with an incidence rate of 0.1 - 0.3 % per live births.PWB results from developmental defects in the dermal vasculature; PWB endothelial cells (ECs) have differentiational impairments.Pulse dye laser (PDL) is currently the preferred treatment for PWB; unfortunately, the efficacy of PDL treatment of PWB has not improved over the past three decades.What does this study add?: Induced pluripotent stem cells (iPSCs) were generated from PWB skin fibroblasts and differentiated into ECs.PWB ECs recapitulated their pathological phenotypes such as forming enlarged blood vessels in vitro and in vivo.Hippo and Wnt pathways were dysregulated in PWB iPSCs and ECs.Zinc-finger family genes were overrepresented among the differentially expressed genes in PWB iPSCs.Dysregulated NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways were enriched in PWB ECs.What is the translational message?: Targeting Hippo and Wnt pathways and Zinc-finger family genes could restore the physiological differentiation of ECs.Targeting NF-kappa B, TNF, MAPK, and cholesterol metabolism pathways could mitigate the pathological progression of PWB.These mechanisms may lead to the development of paradigm-shifting therapeutic interventions for PWB.

Autologous Fat Versus Hydroxyapatite Cement for Use in Frontal Sinus Obliteration: Systematic Review and Meta-Analysis.

BACKGROUND: Frontal sinus obliteration is a possible terminus for the management of chronic sinusitis, frontal bone trauma, cancer extirpation, or mucocele. The mucosa of the sinus is stripped and space obliterated with either autogenic, allopathic, or synthetic materials. This study aimed to compare the outcomes of autologous fat and hydroxyapatite cement (HAC) for frontal sinus obliteration. METHODS: A multidatabase systematic review was conducted to collect outcomes on frontal sinus obliterations with either autologous fat or HAC. Outcomes collected included infection of the frontal sinus or obliteration material, mucocele formation, skin infection at the operative site, hematoma or seroma, cosmetic defect, donor site infection, and need for revision procedure. Prevalence of outcomes was analyzed through meta-analysis of proportions. RESULTS: Twenty studies were ultimately included in the meta-analysis. Sixteen studies reported outcomes for 667 patients obliterated with autologous fat, and 7 studies reported outcomes for 100 patients obliterated with HAC. Prevalence of infection of the frontal sinus or obliteration material, mucocele formation, skin infection at the operative site, hematoma or seroma, and cosmetic defect did not differ statistically between the cohorts. Donor site infection secondary to fat harvesting for fat obliteration had a prevalence of <0.01. Revision rate was 0.04 (95% confidence interval, 0.01-0.8) for fat obliteration and 0.10 (95% confidence interval, 0.00-0.33) for HAC obliteration. CONCLUSIONS: No statistically significant differences in the studied outcomes were detected between obliterations with autologous fat and HAC, suggesting that either is equally suitable and may be up to the surgeon's preference.

Palmar Creases and Their Implication on Carpal Tunnel Surgery.

BACKGROUND: A thorough knowledge of normal and variant anatomy of the wrist and hand is fundamental to avoiding complications during carpal tunnel release. The purpose of this study was to document variations of the surface anatomy of the hand to identify a safe zone in which the initial carpal tunnel incision could be placed. The safe zone was identified as the distance between the radial side of hook of hamate and the ulnar edge of the origin of the motor branch of the median nerve (MBMN). METHODS: Kaplan's cardinal line and other superficial markers were used to estimate the size of the safe zone, in accordance to prior published anatomical studies. The presence of a longitudinal palmar crease (thenar, median, or ulnar creases) within the safe zone was recorded. RESULTS: Of the 150 participants (75 male, 75 female) examined, the average safe zone widths were 10.85 (right) and 10.28 (left) mm. In all the hands examined, 86.33% of the safe zones (259 of 300) contained a longitudinal palmar crease. In the White population (n = 50), the average safe zone widths were 11.49 (right) and 10.01 (left) mm; in the African American population (n = 50), the average safe zone widths were 12.27 (right) and 12.01 (left) mm; and in the Asian population (n = 50), the average safe zone widths were 8.79 (right) and 8.82 (left) mm. On overage, males had a larger safe zone width than females by 4.55 mm. CONCLUSIONS: Although there seems to be variability between race and sex with regard to safe zone width, finding 86.33% of longitudinal palmar creases within the safe zone suggests that, for most patients, the initial carpal tunnel surgery incision may be hidden within the palmar crease while minimizing the risk of motor branch of the median nerve injury. Overall, the safe zone width is on average up to 10.5 mm measured from the hook of the hamate along Kaplan's cardinal line.

The Role of Maximal Locoregional Block in Autologous Breast Reconstruction.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) has become the standard of care in microsurgical breast reconstruction. The current literature provides overwhelming evidence of the benefit of ERAS pathways in improving quality of recovery, decreasing length of hospital stay, and minimizing the amount of postoperative narcotic use in these patients. However, there are limited data on the role of using maximal locoregional anesthetic blocks targeting both the abdomen and chest as an integral part of an ERAS protocol in abdominally based autologous breast reconstruction. The aim of this study is to compare the outcomes of implementing a comprehensive ERAS protocol with and without maximal locoregional nerve blocks to determine any added benefit of these blocks to the standard ERAS pathway. METHODS: Forty consecutive patients who underwent abdominally based autologous breast reconstruction in the period between July 2017 and February 2020 were included in this retrospective institutional review board-approved study. The goal was to compare patients who received combined abdominal and thoracic wall locoregional blocks as part of their ERAS pathway (study group) with those who had only transversus abdominis plane blocks. The primary end points were total hospital length of stay, overall opioids consumption, and overall postoperative complications. RESULTS: The use of supplemental thoracic wall block resulted in a shorter hospital length of stay in the study group of 3.2 days compared with 4.2 days for the control group (P < 0.01). Postoperative total morphine equivalent consumption was lower at 38 mg in the study group compared with 51 mg in the control group (P < 0.01). Complications occurred in 6 cases (15%) in the control group versus one minor complication in the thoracic block group. There was no difference between the 2 groups in demographics, comorbidities, and type of reconstruction. CONCLUSION: The maximal locoregional nerve block including a complete chest wall block confers added benefits to the standard ERAS protocol in microvascular breast reconstruction.

Sternotomy Wound Closure: Equivalent Results with Less Surgery.

BACKGROUND: Mediastinitis after a median sternotomy can be life-threatening. The advent of pedicle flap-based treatment has resulted in an improvement in both morbidity and mortality. However, significant morbidities can still occur following the use of flaps for sternal closure, particularly in patients with comorbidities. To minimize an extensive surgical dissection, we modified our approach to reconstruction using a modified subpectoral approach, leaving the overlying skin attached. This technique focuses primarily on controlling wound tension rather than on maximal muscle coverage. This study is a retrospective review of 58 consecutive patients treated with this approach, by a single surgeon. METHODS: Fifty-eight consecutive patients treated between 2008 and 2019 were included. All patients received the same procedure regardless of the degree of illness, the extent of tissue loss, and the size of sternal defect. Treatment included thorough debridement, with total sternectomy (if required); limited dissection of the pectoralis major muscle off the chest wall to the level of the pectoralis minor without skin and subcutaneous undermining; no release of the insertion of the pectoralis or use of the rectus abdominis; and midline closure over drains connected to wall suction to obliterate dead space. RESULTS: Reoperations were required in 7 patients (12%). Of these, only 4 (6.9%) were related to continued sternal osteomyelitis. The other reoperations were for hematoma evacuation, breast fat necrosis, and skin necrosis. There were no operative mortalities. CONCLUSION: Chest closure using minimal dissection and tension release is safe, efficient, and associated with a complication rate equivalent to more extensive procedures reported in the literature despite significant comorbidities.

Wise Pattern Direct Implant Breast Reconstruction: A Review and Improved Outcomes Using Dermal Matrix.

BACKGROUND: The inverted T (Wise pattern) mastectomy for patients with macromastia or significant breast ptosis has evolved along with generalized techniques for breast reconstruction. We present a review of Wise pattern breast reconstruction along with our technique for direct to implant reconstruction using dermal matrix. METHODS: The literature was reviewed and an analysis of techniques and complications was performed. We present our series of patients incorporating dermal matrix and relatively large implants in direct to implant reconstruction. RESULTS: Of 18 breasts reconstructed only 2 failed. One caused by flap necrosis secondary to smoking and one as a result of preoperative radiation. CONCLUSION: Wise pattern breast reconstruction using relatively large implants and dermal matrix in direct to implant reconstruction is a safe technique in selected patients with macromastia.

Management of regional hidradenitis suppurativa with vacuum-assisted closure and split thickness skin grafts.

BACKGROUND: Hidradenitis suppurativa can be a debilitating chronic illness. The underlying cause of the disease is still not clear, but effective treatment of widespread regional disease relies on resection of all the involved skin and subcutaneous tissue. Closure of the resulting large wound is dependent on either flap or skin graft coverage. Many of the resulting wounds are too large for flap closure or result in unacceptable flap donor site deficits. METHODS: We present a series of 11 patients with 24 regional disease sites treated with a protocol of excision, followed by wound vacuum-assisted closure (VAC; KCI, San Antonio, TX) therapy to stimulate angiogenesis of exposed fat, and then skin grafting with the use of VAC to support the grafts on the recipient sites. RESULTS: Only 3 of the patients required regrafting. One patient had a VAC failure because of poor patient compliance, and 1 patient had 4 sites that each required regrafting as the epithelium would not fill in the residual open areas as it usually did in other patients. All patients were cured of their local disease. CONCLUSIONS: Massive regional hidradenitis suppurativa can be successfully managed with wide excision, VAC therapy, and skin grafting to allow these patients to live normal and productive lives.

Tongue dysmorphology in craniofacial microsomia.

BACKGROUND: Craniofacial microsomia is one of the most common and well-characterized craniofacial anomalies. Tongue dysmorphism, however, has been neither thoroughly investigated nor reported in the context of this disease. This review focuses on the true prevalence of tongue dysmorphology in craniofacial microsomia and its relation to the deformities seen in this condition. METHODS: A 20-year retrospective study was performed to determine the number of patients who had a documented tongue anomaly and any relation to the development of abnormal speech. In recognition of the limitations of this approach, a 1-year prospective study was also performed to see the true prevalence of tongue dysmorphology in these patients. RESULTS: Eight of 167 patients (4.8 percent) in the retrospective study were found to have tongue dysmorphologies, as opposed to 24 of 55 (43.6 percent) in the prospective study. The majority of tongue anomalies were mild. Of the eight retrospective patients, seven currently have intelligible speech with a combination of intensive speech therapy and/or surgical correction. The eighth patient is without intelligible speech. Tongue dysmorphology was positively correlated with the degree of hard- and soft-tissue deformity. CONCLUSIONS: Tongue dysmorphologies in craniofacial microsomia, although usually mild, are frequently overlooked. The correlation of the tongue, soft tissue, and mandible anomalies may point to a common error early in gestation or an interdependence of adjacent growth centers.

Evaluation of the safety of posterior cranial vault reconstruction.

BACKGROUND: Posterior vault reconstruction involves exposure, craniotomy, and reconstruction of the occipital cranium. Although it is commonly performed, the safety and complications associated with posterior vault reconstruction have not been specifically or thoroughly examined. METHODS: A retrospective chart review was performed for all patients undergoing posterior vault reconstruction at the Children's Hospital of Philadelphia between 1996 and 2006. Diagnosis, operative indication, age and weight at time of surgery, procedure type, intraoperative and postoperative complications, estimated blood loss, blood transfusion volume, and length of surgery and admission were recorded. RESULTS: Fifty posterior vault reconstruction cases were included in the study (17 syndromic and 33 nonsyndromic). Mean estimated blood loss was 53.6 percent (range, 15.9 to 142.9 percent) of total blood volume and was statistically greater in syndromic patients (60.6 percent versus 50.0 percent; p = 0.038). Transfusion volume averaged 66.1 percent of total blood volume but was not statistically significant. Length of surgery and number of intraoperative complications were significantly elevated in the syndromic cohort (p = 0.007 and p = 0.037, respectively), whereas length of admission and number of postoperative complications were not. Complications were intraoperative in seven patients (14 percent) and postoperative in seven (14 percent), for an overall complication rate of 28 percent. CONCLUSIONS: This is the largest series to date addressing the safety and complications of posterior vault reconstruction. In the authors' experience, posterior vault reconstruction carries a higher risk of intraoperative complications and blood loss compared with that reported in the literature for other types of cranial vault reconstruction. In addition, syndromic patients were more likely than nonsyndromic patients to encounter intraoperative problems.

Prevention of postsurgery-induced abdominal adhesions by electrospun bioabsorbable nanofibrous poly(lactide-co-glycolide)-based membranes.

OBJECTIVES: The objective of this study was to evaluate the efficacy of nonwoven bioabsorbable nanofibrous membranes of poly(lactideco-glycolide) for prevention of postsurgery-induced abdominal adhesions. SUMMARY BACKGROUND DATA: Recent reports indicated that current materials used for adhesion prevention have only limited success. Studies on other bioabsorbable materials using a new fabrication technique demonstrated the promising potential of generating an improved and inexpensive product that is suitable for a variety of surgical applications. METHODS: All rats underwent a midline celiotomy. The cecum was identified and scored using an abrasive pad until serosal bleeding was noted on the anterior surface. A 1 x 1 cm of abdominal wall muscle was excised directly over the cecal wound. The celiotomy was then closed in 2 layers immediately (control) after a barrier was laid in between the cecum and the abdominal wall. All rats underwent a second celiotomy after 28 days to evaluate the extent of abdominal adhesions qualitatively and quantitatively. RESULTS: Cecal adhesions were reduced from 78% in the control group to 50% in the group using biodegradable poly(lactide-co-glycolide) (PLGA) nonwoven nanofibrous membranes (n = 10, P = 0.2) and to 22% in the group using membranes containing PLGA and poly(ethylene glycol)/poly(D,L-lactide) (PEG-PLA) blends (n = 9, P = 0.03). Electrospinning method also enabled us to load an antibiotic drug Cefoxitin sodium (Mefoxin; Merck Inc., West Point, PA) with high efficacy. The electrospun PLGA/PEG-PLA membranes impregnated with 5 wt% cefoxitin sodium, which amounts to approximately 10% of the systemic daily dose typically taken after surgery in humans, completely prevented cecal adhesions (0%) in rats. CONCLUSIONS: Electrospun nonwoven bioabsorbable nanofibrous membranes of poly(lactide-co-glycolide) were effective to reduce adhesions at the site of injury using an objective rat model. The membrane acted as a physical barrier but with drug-delivery capability. The combined advantages of composition adjustment, drug-loading capability, and easy placement handling (relatively hydrophobic) make these membranes potentially successful candidates for further clinical evaluations.

Role of chemically modified tetracycline on TNF-alpha and mitogen-activated protein kinases in sepsis.

Chemically modified tetracyclines are orally active inhibitors of multiple proteases and cytokines. In this study, we focused on the regulation of tumor necrosis factor (TNF)-alpha and mitogen-activated protein kinases (MAPKs) in sepsis and their reduction by treatment with nonantimicrobial chemically modified tetracycline-3 (CMT-3), which retains their antiinflammatory activity. Sepsis was induced in rats by cecal ligation and puncture (CLP). At 24 h and 1 h before CLP, treated rats received CMT-3 (25 mg/kg), and untreated rats received saline by gavage. At 0 h, 0.5 h, 1.5 h, and 24 h after CLP, blood and liver samples were collected. TNF-alpha was determined by ELISA, and MAPKs were determined by Western blot analysis. A significant activation of p38 MAPK was observed after 0.5 h and 1.5 h of sepsis that appeared to coincide with the increased circulating TNF-alpha level. The activation of p42/44 was increased after 24 h of sepsis, whereas that of SAPK/JNK was unaltered throughout the course of sepsis. CMT-3 pretreatment inhibited the TNF-alpha level as well as p38 MAPK activation seen after 0.5 and 1.5 h of CLP and also suppressed the activation of p42/44 after 24 h post-CLP. These results indicate increased activity of TNF-alpha and MAPK following sepsis and demonstrate the beneficial effect of CMT-3 in preventing the increase in TNF-alpha, p38 MAPK, p42/44 MAPK, and the progression of septic shock.

Modulations of signal transduction pathways during sepsis and the effects of insulin and mifepristone.

OBJECTIVES: The phosphorylation states and the inferred activation of specific members of the mitogen-activated protein kinase (MAPK) pathways (p42/44, p38, and SAPK/JNK) were quantitated in the livers of rats by Western blot analysis during the progression of sepsis. In addition, the authors examined the effects of insulin and mifepristone (RU-486) administration on these signal transduction pathways during sepsis. METHODS: Sepsis was brought about by the cecal ligation and puncture (CLP) method. The control group underwent sham operation. One experimental group was injected with insulin (0.5 U/kg, IV); prior to the CLP or sham procedure, the second group was injected with RU-486, a glucocorticoid antagonist (mifepristone, 20 mg/kg, IP), and the third group was injected with saline (control). RESULTS: The activities of SAPK/JNK were unaltered throughout the course of sepsis, while those of p42/44 MAPK increased four-fold after 24 hours of sepsis. The activation of p38 MAPK was also increased after 0.5 and 1.5 hours of sepsis, but returned to normal during late sepsis (24 hours). Rats that had received RU-486 before CLP showed no change in p42/44 MAPK compared with the untreated group, but the drug appeared to suppress the activation after 24 hours post-CLP. SAPK/JNK activation, on the other hand, was slightly enhanced by RU-486 pretreatment after 1.5 and 24 hours of CLP compared with the untreated CLP and the treated sham-operated rats. Insulin, given preoperatively, had no effect on the activation of SAPK/JNK, although p42/44 MAPK pathways were activated by the hormone at 0.5 hours and 1.5 hours post-CLP only, but not in the sham-operated controls or at 24 hours post-CLP. The p38 MAPK activation seen after 0.5 and 1.5 hours of CLP was suppressed by RU-486. Insulin pretreatment appears to suppress the phosphorylation of p38 in both the CLP and sham-operated groups. CONCLUSIONS: The data suggest that sepsis induces two phases of MAPK activation, an early phase in which p38 is active, followed by a second, more pronounced phase of p42/44 MAPK activation that occurs only late in sepsis. Hormonal administration results suggest that RU-486 suppresses the activation of p38 seen in early sepsis, and the activation of p42/44 MAPK seen in late sepsis.