Prenatal Diagnosis of Fetal Aqueductal Stenosis: A Multicenter Prospective Observational Study through the North American Fetal Therapy Network.

INTRODUCTION: A critical component of an evidence-based reassessment of in-utero intervention for fetal aqueductal stenosis (fetal AS) is determining if the prenatal diagnosis can be accurately made at a gestational age amenable to in-utero intervention. METHODS: A multicenter, prospective, observational study was conducted through the North American Fetal Therapy Network (NAFTNet). Pregnancies complicated by severe central nervous system (CNS) ventriculomegaly (lateral ventricle diameter >15 mm) not secondary to a primary diagnosis (myelomeningocele, encephalocele, etc.) were recruited at diagnosis. Imaging and laboratory findings were recorded in an online REDCap database. After evaluation, investigators were asked to render their degree of confidence in the diagnosis of fetal AS. The prenatal diagnosis was compared to the postnatal diagnosis obtained through neonatal neuroimaging. Performance characteristics of ultrasound and magnetic resonance imaging (MRI) were calculated, as was the mean gestational age at diagnosis. RESULTS: Between April 2015 and October 2022, eleven NAFTNet centers contributed 64 subjects with severe fetal CNS ventriculomegaly. Of these, 56 had both prenatal and postnatal diagnoses recorded. Ultrasound revealed 32 fetal AS true positives, 4 false positives, 7 false negatives, and 13 true negatives, rendering a sensitivity of 0.82, a specificity of 0.76, a positive predictive value of 0.89, and a negative predictive value of 0.65. The mean gestational age at diagnosis by ultrasound was 25.5 weeks (std +/- 4.7 weeks). The proportion of agreement (true positive + true negative/n) was highest at 24 weeks gestation. For fetal MRI (n = 35), the sensitivity for fetal AS was 0.95, specificity was 0.69, positive predictive value was 0.84, and negative predictive value was 0.90. MRI was performed at 25 weeks on average. CONCLUSION: The prenatal diagnosis of fetal AS can be made with accuracy at a gestational age potentially amenable to in-utero intervention. Only 7% of subjects were incorrectly diagnosed prenatally with fetal AS by ultrasound and 11% by MRI. Diagnostic accuracy of fetal AS will likely improve with increased experience.

Postdischarge Opioid Prescription after Cesarean: A Quality Improvement Initiative.

OBJECTIVE: This study aims to determine if adoption of a user-friendly algorithm for individualized opioid prescribing at discharge would decrease the number of opioids prescribed after cesarean delivery. STUDY DESIGN: As part of a quality initiative, we developed and implemented an algorithm for opioid prescribing at discharge for patients after cesarean delivery. The intervention group comprised patients delivering by cesarean in the 6 months following initiation of the intervention. The intervention group was divided into three groups based on inpatient opioid needs 24 to 48 hours after delivery. Oxycodone tablets were prescribed at discharge based on inpatient group. The control group comprised patients delivering at the same institution in the 6 months prior to initiation of the intervention. The primary outcome was number of oxycodone tablets prescribed at discharge. The secondary outcome was the proportion of patients with a pain-related encounter or additional oxycodone prescription up to 6 weeks after delivery. RESULTS: From July to December 2020, a total of 382 subjects met criteria for the intervention. The comparison group consisted of 391 subjects discharged from January to June 30, 2020, after cesarean. Baseline characteristics and inpatient opioid use 24 to 48 hours after delivery did not differ between the groups. Compared with the control group, subjects in the intervention group had fewer oxycodone tablets prescribed at discharge (11.1 vs. 15.8, p < 0.001). The number of pain-related encounters within 6 weeks of delivery did not differ between the intervention and comparison groups (10.5 vs. 10.3%, p = 0.82). There was no increase in the additional number of oxycodone prescriptions after discharge (4.7% in the intervention group vs. 4.3% in the control group, p = 0.81). CONCLUSION: Discharge opioid prescribing based on inpatient use after cesarean reduces the number of opioids prescribed without increasing the number of pain-related encounters after discharge. A simple algorithm may ensure compliance from prescribers. KEY POINTS: · Previous research has shown that most opioids prescribed after cesarean delivery are unused after discharge. We implemented an algorithm for opioid discharge prescribing after cesarean delivery based on inpatient opioid consumption.. · Implementing an individualized approach to opioid prescribing reduced the number of tablets prescribed at discharge after cesarean delivery. The decrease in discharge prescribing did not correspond to an increase in pain-related encounters or additional narcotic prescriptions in the 6 weeks following delivery.. · The overprescription of opioids at discharge after cesarean delivery is well-established, and previous authors have found success in prescribing opioids at discharge based on inpatient use. Our study proposes a simple, reproducible algorithm for opioid prescribing at discharge after cesarean..

The association between gestational age at delivery, closure type and perinatal outcomes in neonates with isolated gastroschisis.

Objective: The objective of this study was to examine the association between gestational age at delivery and closure type for neonates with gastroschisis. In addition, we compared perinatal outcomes among the cases of gastroschisis based on the following two factors: gestational age at delivery and abdominal wall closure technique.Methods: This was a retrospective cohort study of all fetuses with isolated gastroschisis that were diagnosed prenatally and delivered between September 2000 and January 2017, in a single tertiary care center. Neonates were compared based on the gestational age at the time of delivery: early preterm (less than 350/7 weeks), late preterm (350/7 - 366/7 weeks), and early term (370/6 - 386/7 weeks), using bivariate and multivariate analyses. The primary outcome was the type of abdominal wall closure: primary surgical closure or delayed closure using spring-loaded silo. Secondary outcomes included length of ventilatory support, length of parenteral nutrition, and length of hospital stay.Results: The analysis included 206 pregnancies complicated by gastroschisis. In univariate analysis, no differences were detected in primary closure rates of gastroschisis among the gestational age at delivery groups (67.4%, at <35 weeks, 70.8% at 350/7-366/7 weeks, 73.7% at 370/6-386/7 weeks, p = .865). However, for every additional 100 grams of neonatal live birth weight there was an associated 9% increased odds of primary closure (OR 1.09, 95% CI 1.14-1.19, p = .04). Delivery in the early preterm period compared to the other two groups, was associated with longer duration of ventilation support and longer dependence on the parenteral nutrition. Neonates who underwent primary closure had shorter ventilation support, shorter time to initiation of enteral feeds and to discontinue parenteral nutrition, and shorter length of stay. In multivariate analyses, controlling for gestational age at delivery and presence of bowel atresia, primary closure continued to be associated with the shorter duration of ventilation (by 5 days), earlier initiation of enteral feeds (by 7 days), shorter hospital stay (by 17 days) and lower odds of wound infection (OR = 0.37, 95% CI 0.15-0.97).Conclusions: Our study did not find an association between gestational age at delivery and the rates of primary closure of the abdominal wall defect; however later gestational age at delivery was associated with shorter duration of ventilatory support and parenteral nutrition dependence. In addition, we found that primary closure of gastroschisis, compared with delayed closure technique, was associated with improved neonatal outcomes, including shorter time to initiate enteral feeds and discontinue parenteral nutrition, shorter hospital stay, and lower risk of surgical wound infection. Therefore, postponing delivery of fetuses with gastroschisis until 37 weeks may be considered. Other factors besides the gestational age at delivery should be explored as predictors of primary closure in neonates with gastroschisis.

National Practice Patterns for Prenatal Monitoring in Gastroschisis: Gastroschisis Outcomes of Delivery (GOOD) Provider Survey.

BACKGROUND: Gastroschisis is an abdominal wall defect with increasing incidence. Given the lack of surveillance guidelines among maternal-fetal medicine (MFM) specialists, this study describes current practices in gastroschisis management. MATERIALS AND METHODS: An online survey was administered to MFM specialists from institutions affiliated with the North American Fetal Therapy Network (NAFTNet). Questions focused on surveillance timing, testing, findings that changed clinical management, and delivery plan. RESULTS: Responses were obtained from 29/29 (100%) NAFTNet centers, comprising 143/371 (39%) providers. The majority had a regimen for antenatal surveillance in patients with stable gastroschisis (94%; 134/141). Antenatal testing began at 32 weeks for 68% (89/131) of MFM specialists. The nonstress test (55%; 72/129), biophysical profile (50%; 63/126), and amniotic fluid index (64%; 84/131) were used weekly. Estimated fetal weight (EFW) was performed monthly by 79% (103/131) of providers. At 28 weeks, abnormal EFW (77%; 97/126) and Doppler ultrasound (78%; 99/127) most frequently altered management. In stable gastroschisis, 43% (60/140) of providers delivered at 37 weeks, and 29% (40/ 140) at 39 weeks. DISCUSSION: Gastroschisis management differs among NAFTNet centers, although the majority initiate surveillance at 32 weeks. Timing of delivery still requires consensus. Prospective studies are necessary to further optimize practice guidelines and patient care.

Prenatal counseling and parental decision-making following a fetal diagnosis of trisomy 13 or 18.

OBJECTIVES: To evaluate parental decisions following a prenatal diagnosis of trisomy 13 (T13) or trisomy 18 (T18), prenatal counseling received, and pregnancy outcomes. STUDY DESIGN: Single-center, retrospective cohort study of families with a prenatal diagnosis of T13 or T18 from 2000 to 2016. RESULTS: Out of 152 pregnancies, 55% were terminated. Twenty percent chose induction with palliative care, 20% chose expectant management, 2% chose full interventions, and 3% were lost to follow-up. Counseling was based on initial parental goals, but most women were given options besides termination. Women who chose expectant management had a live birth in 50% of the cases. Women who chose neonatal interventions had a live birth in 100% of the cases, but there were no long-term survivors. CONCLUSIONS: The majority of women who continue their pregnancy after a fetal diagnosis of T13 or T18 desire expectant management with palliative care. A live birth can be expected at least half of the time.

Meconium-stained amniotic fluid as a predictor of poor outcomes in gastroschisis.

OBJECTIVE: The aim of this study was to determine if meconium-stained amniotic fluid (MSAF) was associated with neonatal outcomes in gastroschisis. STUDY DESIGN: A retrospective chart review of gastroschisis patients from 2000 to 2014 at a single, tertiary institution was performed. Statistical analysis was performed with Fisher exact test, Welch's t-test, logistic regression and/or linear regression with significance at p < 0.05. RESULTS: Sixty-four of 135 (47.4%) gastroschisis patients had MSAF. On univariate analysis, patients with MSAF were more likely to require staged closure (30 (46.9%) vs. 18(25.4%), p = 0.012), had more ventilator days (8.9 ±â€¯11.1 vs. 5.3 ±â€¯6.3, p = 0.021) and longer times to commence enteral feeds (24.9 ±â€¯21.7 vs. 18.5 ±â€¯14.5, p = 0.045). However, multi-variate regression analysis controlling for the type of closure, showed that delayed closure, but not MSAF, was associated with worse outcomes. CONCLUSIONS: In gastroschisis patients, MSAF is associated with delayed closure but is not associated with outcomes independent of closure type. This association may be because of the matting of the bowel or increased intestinal damage. The MSAF status will aid in setting expectations for parents during their initial NICU stay and further investigation is warranted. TYPE OF STUDY: Clinical Research Paper Level of evidence: III.

Cancer in Pregnancy.

This article reviews some of the more common types of cancer that may be encountered during pregnancy. It reviews the unique challenges with the diagnosis and treatment of breast, cervical, hematologic, and colon cancers in pregnant patients.

The significance of organ prolapse in gastroschisis.

PURPOSE: The aim of this study was to evaluate the incidence and importance of organ prolapse (stomach, bladder, reproductive organs) in gastroschisis. METHODS: This is a retrospective review of gastroschisis patients from 2000 to 2014 at a single tertiary institution. Statistical analysis was performed using a chi-square test, Student's t test, log-rank test, or Cox regression analysis models. All tests were conducted as two-tailed tests, and p-values <0.05 were considered statistically significant. RESULTS: One hundred seventy-one gastroschisis patients were identified. Sixty-nine (40.6%) had at least one prolapsed organ besides bowel. The most commonly prolapsed organs were stomach (n=45, 26.3%), reproductive organs (n=34, 19.9%), and bladder (n=15, 8.8%). Patients with prolapsed organs were more likely to have simple gastroschisis with significant decreases in the rate of atresia and necrosis/perforation. They progressed to earlier enteral feeds, discontinuation of parenteral nutrition, and discharge. Likewise, these patients were less likely to have complications such as central line infections, sepsis, and short gut syndrome. CONCLUSIONS: Gastroschisis is typically described as isolated bowel herniation, but a large portion have prolapse of other organs. Prolapsed organs are associated with simple gastroschisis, and improved outcomes most likely due to a larger fascial defect. This may be useful for prenatal and postnatal counseling of families. TYPE OF STUDY: Case Control/Retrospective Comparative Study. LEVEL OF EVIDENCE: Level III.

Clinical Evidence for Spinal Cord Stimulation for Failed Back Surgery Syndrome (FBSS): Systematic Review.

STUDY DESIGN: A systematic review. OBJECTIVE: A systematic literature review of the clinical data from prospective studies was undertaken to assess the efficacy of spinal cord stimulation (SCS) in the treatment of failed back surgery syndrome (FBSS) in adults. SUMMARY OF BACKGROUND DATA: For patients with unrelenting back pain due to mechanical instability of the spine, degenerative disc disease, spinal injury, or deformity, spinal surgery is a well-accepted treatment option; however, even after surgical intervention, many patients continue to experience chronic back pain that can be notoriously difficult to treat. Clinical evidence suggests that for patients with FBSS, repeated surgery will not likely offer relief. Additionally, evidence suggests long-term use of opioid pain medications is not effective in this population, likely presents additional complications, and requires strict management. METHODS: A systematic literature review was performed using several bibliographic databases, prospective studies in adults using SCS for FBSS were included. RESULTS AND CONCLUSION: SCS has been shown to be a safe and efficacious treatment for this patient population. Recent technological developments in SCS offer even greater pain relief to patients' refractory to other treatment options, allowing patients to regain functionality and improve their quality of life with significant reductions in pain. LEVEL OF EVIDENCE: N/A.

Can omphalocele ratio predict postnatal outcomes?

BACKGROUND: The clinical course of patients with omphalocele is challenging to predict. There is no standard method to characterize omphalocele size. Previous studies suggest that the ratio of abdominal circumference to omphalocele defect in-utero is indicative of postnatal outcomes. We hypothesize that omphalocele ratio correlates with outcomes of primary closure versus staged closure. METHODS: A retrospective chart review of all neonates diagnosed with omphalocele from 2002 to 2013 with prenatal ultrasounds available (n=30) was conducted. Omphalocele ratio was defined as omphalocele diameter/abdominal circumference (OD/AC). Data collected included primary versus staged closure, time to full feeds, duration of mechanical ventilation, and length of stay (LOS). Long-term outcomes and quality of life were also reported. RESULTS: ROC curve analysis generated optimal OD/AC ratio of 0.26. Twenty of 30 patients had a ratio less than this cutoff. Sixty percent (12/20) in the low-ratio group achieved primary closure versus zero (0/10) in the high-ratio group (p=0.001). Time on mechanical ventilation was 15.8 days (low-ratio) versus 79 days (high-ratio) (p=0.05). LOS was 33.8 days (low-ratio) versus 85.6 days (high-ratio) (p=0.119). PedsQL™ mean score was 85.5 ± 11.0 (n=20) at long-term follow-up. Readmission rates yielded no difference. CONCLUSIONS: The omphalocele ratio is a promising predictor of postnatal outcomes.

An unusual occurrence: a case of venous thromboembolism in pregnancy associated with heterotaxy syndrome.

BACKGROUND: Heterotaxy is a relatively uncommon congenital anomaly that is usually diagnosed incidentally on imaging studies in adults. We present an unusual case of venous thromboembolism in a 26 year old pregnant female with Heterotaxy syndrome. CASE PRESENTATION: A 26 year-old pregnant female at 13 weeks gestation suffered cardiac arrest with successful cardiac resuscitation and return of spontaneous circulation. The cardiac arrest was secondary to massive pulmonary embolism requiring thrombolytic therapy and stabilization of hemodynamics. She had extensive evaluation to determine the etiology for the pulmonary embolism and was noted to have an anatomic variation consistent with heterotaxy syndrome on imaging studies. After thrombolysis the patient was treated with UFH and then switched to enoxaparin without complication until 25 weeks of gestation when she experienced worsening abdominal pain with associated headaches, lightheadedness and elevated blood pressures needing elective induction of labor. The infant died shortly after delivery. The anticoagulation was continued for additional 3 months and she was subsequently placed on low dose aspirin to prevent recurrent venous thromboembolic episodes. She is currently stable on low dose aspirin and is into her third year after the venous thromboembolism without any recurrence. CONCLUSION: To our knowledge, this is the first reported case of venous thromboembolism in pregnancy associated with heterotaxy syndrome. A discussion on pathophysiology of venous thromboembolism in pregnancy and heterotaxy syndrome has been undertaken along with treatment approach in such situations.

Percutaneous in utero thoracoamniotic shunt creation for fetal thoracic abnormalities leading to nonimmune hydrops.

PURPOSE: To describe a transabdominal, transuterine Seldinger-based percutaneous approach to create a shunt for treatment of fetal thoracic abnormalities. MATERIALS AND METHODS: Five fetuses presented with nonimmune fetal hydrops secondary to fetal thoracic abnormalities causing severe mass effect. Under direct ultrasound guidance, an 18-gauge needle was used to access the malformation. Through a peel-away sheath, a customized pediatric transplant 4.5-F double J ureteral stent was advanced; the leading loop was placed in the fetal thorax, and the trailing end was left outside the fetal thorax within the amniotic cavity. RESULTS: Seven thoracoamniotic shunts were successfully placed in five fetuses; one shunt was immediately replaced because of displacement during the procedure, and another shunt was not functioning at follow-up requiring insertion of a second shunt. All fetuses had successful decompression of the thoracic malformation, allowing lung reexpansion and resolution of hydrops. Three of five mothers had meaningful (> 7 d) prolongation of their pregnancies. All pregnancies were maintained to > 30 weeks (range, 30 weeks 1 d-37 weeks 2 d). There were no maternal complications. CONCLUSIONS: A Seldinger-based percutaneous approach to draining fetal thoracic abnormalities is feasible and can allow for prolongation of pregnancy and antenatal lung development and ultimately result in fetal survival.

Placenta increta after hysteroscopic myomectomy.

BACKGROUND: Most cases of abnormal placentation are associated with a history of one or more cesarean deliveries. Uterine leiomyomas and treatment for such a diagnosis are also risk factors for placenta accreta and should be viewed as such. CASE: A 34-year-old woman underwent a hysteroscopic myomectomy and became pregnant 6 months later. Ultrasonography and magnetic resonance imaging suggested a placenta percreta. Multidisciplinary care allowed for a safe delivery of her neonate and little maternal morbidity. CONCLUSION: Patients with a history of hysteroscopic myomectomy or other uterine leiomyoma treatment are at an increased risk for abnormal placentation. Imaging studies are suggested in such patients to coordinate multidisciplinary care to decrease maternal and fetal morbidity and mortality.

A critical review of early-onset and late-onset preeclampsia.

UNLABELLED: Preeclampsia is a leading cause of pregnancy-related morbidity and mortality in the United States. In the past 30 years, a large amount of research has been performed to investigate the pathogenesis and pathophysiology of preeclampsia, ways to treat preeclampsia, markers that can be used to predict preeclampsia, and associations with other factors, such as smoking, stroke, and cardiovascular disease. Preeclampsia has been characterized by some investigators into 2 different disease entities: early-onset preeclampsia and late-onset preeclampsia. Early-onset preeclampsia is usually defined as preeclampsia that develops before 34 weeks of gestation, whereas late-onset preeclampsia develops at or after 34 weeks of gestation. Although the presenting features overlap, they are associated with different maternal and fetal outcomes, biochemical markers, heritability, and clinical features. To date, no review has analyzed the data focusing on early- versus late-onset preeclampsia. This review summarizes the relevant research on the similarities and differences between early- and late-onset preeclampsia as it relates to pathogenesis and biomarkers, including differences in vascular endothelial growth factor, placental growth factor, vascular endothelial growth factor receptor-1, epidermal growth factor, transforming growth factor-ß, vascular cell adhesion molecule, toll-like receptor, plasma pentraxin 3, soluble endoglin, and lipid peroxidation. Although many articles have been published regarding these 2 entities, more data regarding differences and similarities between the 2 are clearly needed. Such study should permit more effective diagnosis, treatment, and management of patients with preeclampsia. TARGET AUDIENCE: Obstetricians & Gynecologists and Family Physicians Learning Objectives: After the completing the CME activity, physicians should be better able to evaluate the role of abnormal placentation in preeclampsia. Develop a protocol for researching biomarkers relevant to early-onset and late-onset preeclampsia. To distinguish the biomarkers that are similar and different in early-onset and late-onset preeclampsia.

Risk factors for postpartum antihypertensive medication requirement in severe preeclampsia.

OBJECTIVE: To determine antepartum risk factors for postpartum antihypertensive medication use in women with severe preeclampsia. METHODS: A case control study was performed on patients who were diagnosed with severe preeclampsia between January 2000 and June 2004 at a single tertiary care center. Women discharged from the hospital on antihypertensive medications were compared to women discharged home on no antihypertensive medications. Demographic data, maternal medical conditions, and delivery data were abstracted from maternal charts. Risk factors were evaluated using multiple logistic regression. RESULTS: 218 patients with severe preeclampsia were identified, of which 112 were discharged on antihypertensives. After adjusting for confounding variables, chronic hypertension was associated with an increased need for post partum antihypertensive medication (OR 7.5 (95% CI 3.0-18.1)). A dose-dependent association was seen with intrapartum hydralazine administration. High-dose hydralazine was associated with increased need for postpartum antihypertensive mediation (OR 5.74 95% CI 2.03-16.2) compared to low-dose hydralazine (OR of 2.51 95% CI 1.26-5.01). Hemolysis/Elevated liver function/low platelet (HELLP) syndrome was associated with a decreased need for antihypertensive medication (OR 0.33, 95% CI 0.13-0.82). CONCLUSIONS: Patients with chronic hypertension and patients who required intrapartum hydralazine were more likely to require antihypertensive medications at discharge.

Mercury induces inflammatory mediator release from human mast cells.

BACKGROUND: Mercury is known to be neurotoxic, but its effects on the immune system are less well known. Mast cells are involved in allergic reactions, but also in innate and acquired immunity, as well as in inflammation. Many patients with Autism Spectrum Disorders (ASD) have "allergic" symptoms; moreover, the prevalence of ASD in patients with mastocytosis, characterized by numerous hyperactive mast cells in most tissues, is 10-fold higher than the general population suggesting mast cell involvement. We, therefore, investigated the effect of mercuric chloride (HgCl2) on human mast cell activation. METHODS: Human leukemic cultured LAD2 mast cells and normal human umbilical cord blood-derived cultured mast cells (hCBMCs) were stimulated by HgCl2 (0.1-10 microM) for either 10 min for beta-hexosaminidase release or 24 hr for measuring vascular endothelial growth factor (VEGF) and IL-6 release by ELISA. RESULTS: HgCl2 induced a 2-fold increase in beta-hexosaminidase release, and also significant VEGF release at 0.1 and 1 microM (311 +/- 32 pg/106 cells and 443 +/- 143 pg/106 cells, respectively) from LAD2 mast cells compared to control cells (227 +/- 17 pg/106 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 microM) to the proinflammatory neuropeptide substance P (SP, 0.1 microM) had synergestic action in inducing VEGF from LAD2 mast cells. HgCl2 also stimulated significant VEGF release (360 +/- 100 pg/106 cells at 1 microM, n = 5, p < 0.05) from hCBMCs compared to control cells (182 +/- 57 pg/106 cells), and IL-6 release (466 +/- 57 pg/106 cells at 0.1 microM) compared to untreated cells (13 +/- 25 pg/106 cells, n = 5, p < 0.05). Addition of HgCl2 (0.1 microM) to SP (5 microM) further increased IL-6 release. CONCLUSIONS: HgCl2 stimulates VEGF and IL-6 release from human mast cells. This phenomenon could disrupt the blood-brain-barrier and permit brain inflammation. As a result, the findings of the present study provide a biological mechanism for how low levels of mercury may contribute to ASD pathogenesis.

IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin.

The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1-10 microM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5-100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component.