Contemporary Costs Associated With Transcatheter Versus Surgical Aortic Valve Replacement in Medicare Beneficiaries.

BACKGROUND: In patients with severe aortic stenosis, treatment with transcatheter aortic valve replacement (TAVR) has been shown to be cost-effective in the high-risk surgical population and cost-saving in the intermediate-risk population when compared with surgical aortic valve replacement (SAVR) in early pivotal clinical trials. Whether TAVR is associated with comparable or lower costs when compared with SAVR in contemporary clinical practice is unknown. METHODS: Using data from the Medicare Dataset Standard Analytic Files 5% Fee for Service database, patients receiving either TAVR or SAVR between 2016 and 2018 were identified. Patients were categorized as low, intermediate, or high mortality risk based on 2 validated indices-the Hospital Frailty Risk Score and the logEuroScore. Health care costs out to 1 year were compared between TAVR and SAVR among the low, intermediate, and high-risk groups, after adjustment for patient demographics. RESULTS: Nine thousand seven hundred forty-six patients were identified (4834 TAVR; 3760 SAVR) and included in the analysis. Patients receiving TAVR were older and more likely to be female. Index hospitalization costs were significantly lower with TAVR compared with SAVR across all risk strata (logEuroScore: low: $61 845 versus $68 986; intermediate: $64 658 versus $76 965; high: $65 594 versus $91 005; P<0.001 for all). Follow-up costs through 1 year were generally lower with TAVR and this difference was more pronounced in the low risk groups (logEuroScore: $9763 versus $14 073; Hospital Frailty Risk Score: $10 116 versus $12 880). Accordingly, cumulative 1-year costs were substantially lower with TAVR compared with SAVR. CONCLUSIONS: At 1 year, TAVR is associated with lower health care costs across all risk strata when compared with SAVR in contemporary practice. If long-term data continue to demonstrate similar clinical outcomes and valve durability with TAVR and SAVR, these findings suggest that TAVR may be the preferred treatment strategy for patients with aortic stenosis from an economic standpoint.

Temporal Changes in Mortality After Transcatheter and Surgical Aortic Valve Replacement: Retrospective Analysis of US Medicare Patients (2012-2019).

Background The treatment of aortic stenosis is evolving rapidly. Pace of change in the care of patients undergoing transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) differs. We sought to determine differences in temporal changes in 30-day mortality, 30-day readmission, and length of stay after TAVR and SAVR. Methods and Results We conducted a retrospective cohort study of patients treated in the United States between 2012 and 2019 using data from the Medicare Data Set Analytic File 100% Fee for Service database. We included consecutive patients enrolled in Medicare Parts A and B and aged ≥65 years who had SAVR or transfemoral TAVR. We defined 3 study cohorts, including all SAVR, isolated SAVR (without concomitant procedures), and elective isolated SAVR and TAVR. The primary end point was 30-day mortality; secondary end points were 30-day readmission and length of stay. Statistical models controlled for patient demographics, frailty measured by the Hospital Frailty Risk Score, and comorbidities measured by the Elixhauser Comorbidity Index (ECI). Cox proportional hazard models were developed with TAVR versus SAVR as the main covariates with a 2-way interaction term with index year. We repeated these analyses restricted to full aortic valve replacement hospitals offering both SAVR and TAVR. The main study cohort included 245 269 patients with SAVR and 188 580 patients with TAVR, with mean±SD ages 74.3±6.0 years and 80.7±6.9 years, respectively, and 36.5% and 46.2% female patients, respectively. Patients with TAVR had higher ECI scores (6.4±3.6 versus 4.4±3) and were more frail (55.4% versus 33.5%). Total aortic valve replacement volumes increased 61% during the 7-year span; TAVR volumes surpassed SAVR in 2017. The magnitude of mortality benefit associated with TAVR increased until 2016 in the main cohort (2012: hazard ratio [HR], 0.76 [95% CI, 0.67-0.86]; 2016: HR, 0.39 [95% CI, 0.36-0.43]); although TAVR continued to have lower mortality rates from 2017 to 2019, the magnitude of benefit over SAVR was attenuated. A similar pattern was seen with readmission, with a lower risk of readmission from 2012 to 2016 for patients with TAVR (2012: HR, 0.68 [95% CI, 0.63-0.73]; 2016: HR, 0.43 [95% CI, 0.41-0.45]) followed by a lesser difference from 2017 to 2019. Year over year, TAVR was associated with increasingly shorter lengths of stay compared with SAVR (2012: HR, 1.91 [95% CI, 1.84-1.98]; 2019: HR, 5.34 [95% CI, 5.22-5.45]). These results were consistent in full aortic valve replacement hospitals. Conclusions The rate of improvement in TAVR outpaced SAVR until 2016, with the recent presence of U-shaped phenomena suggesting a narrowing gap between outcomes. Future longitudinal research is needed to determine the long-term implications of lowering risk profiles across treatment options to guide case selection and clinical care.

The need for future coronary access following surgical or transcatheter aortic valve replacement.

The aim of the study was to estimate the percentage of Medicare patients needing coronary access for percutaneous coronary intervention (PCI) or coronary angiography following aortic valve replacement (AVR). Indications for TAVR have expanded to include younger and low-risk patients, raising the question of coronary access for future procedures. Medicare patients <80 years old with an AVR between 2011 and 2018 were included. Time-to-event analyses were conducted using Cox hazard models to estimate risk of coronary access up to 7 years after AVR. Model adjustments included age, sex, race, region, comorbidity, concomitant CABG, and smoking. A total of 13,469 Medicare patients (mean age 70.6) met inclusion criteria. Models estimated that 2.5% of patients at 1-year post-index and 17% at over 7 years would need coronary access. For patients who had SAVR (with or without CABG), estimates for coronary access were similar and over 15% after 6.5 years. For TAVR patients, with a previous PCI, 28% at 4.5 years required coronary access, which was higher than TAVR patients without a previous PCI. SAVR patients with and without CAD at baseline were similar; however, TAVR patients with CAD had a 22% rate of coronary access versus 7% for those without at 3 years. Approximately half of patients who needed coronary access returned to the same hospital as their initial AVR. Coronary access is required in a substantial portion of AVR patients especially those with PCI or a history of CAD undergoing TAVR. The need for coronary access may increase as transcatheter AVR becomes accessible to younger patients with a longer life expectancy.

Renal defects associated with improper polarization of the CRB and DLG polarity complexes in MALS-3 knockout mice.

Kidney development and physiology require polarization of epithelia that line renal tubules. Genetic studies show that polarization of invertebrate epithelia requires the crumbs, partition-defective-3, and discs large complexes. These evolutionarily conserved protein complexes occur in mammalian kidney; however, their role in renal development remains poorly defined. Here, we find that mice lacking the small PDZ protein mammalian LIN-7c (MALS-3) have hypomorphic, cystic, and fibrotic kidneys. Proteomic analysis defines MALS-3 as the only known core component of both the crumbs and discs large cell polarity complexes. MALS-3 mediates stable assembly of the crumbs tight junction complex and the discs large basolateral complex, and these complexes are disrupted in renal epithelia from MALS-3 knockout mice. Interestingly, MALS-3 controls apico-basal polarity preferentially in epithelia derived from metanephric mesenchyme, and defects in kidney architecture owe solely to MALS expression in these epithelia. These studies demonstrate that defects in epithelial cell polarization can cause cystic and fibrotic renal disease.

Synaptic transmission regulated by a presynaptic MALS/Liprin-alpha protein complex.

Neurotransmission requires proper organization of synaptic vesicle pools and rapid release of vesicle contents upon presynaptic depolarization. Genetic studies have begun to reveal a critical role for scaffolding proteins in such processes. Mutations in genes encoding components of the highly conserved MALS/CASK/Mint-1 complex cause presynaptic defects. In all three mutants, neurotransmitter release is reduced in a manner consistent with aberrant vesicle cycling to the readily releasable pool. Recently, liprin-alpha proteins, which define active zone size and morphology, were found to associate with MALS/CASK, suggesting that this complex links the presynaptic release machinery to the active zone, thereby regulating neurotransmitter release.

Neurotransmitter release regulated by a MALS-liprin-alpha presynaptic complex.

Synapses are highly specialized intercellular junctions organized by adhesive and scaffolding molecules that align presynaptic vesicular release with postsynaptic neurotransmitter receptors. The MALS/Veli-CASK-Mint-1 complex of PDZ proteins occurs on both sides of the synapse and has the potential to link transsynaptic adhesion molecules to the cytoskeleton. In this study, we purified the MALS protein complex from brain and found liprin-alpha as a major component. Liprin proteins organize the presynaptic active zone and regulate neurotransmitter release. Fittingly, mutant mice lacking all three MALS isoforms died perinatally with difficulty breathing and impaired excitatory synaptic transmission. Excitatory postsynaptic currents were dramatically reduced in autaptic cultures from MALS triple knockout mice due to a presynaptic deficit in vesicle cycling. These findings are consistent with a model whereby the MALS-CASK-liprin-alpha complex recruits components of the synaptic release machinery to adhesive proteins of the active zone.

Report of a patient with severe transfusion-related acute lung injury after multiple transfusions, resuscitated with albumin.

OBJECTIVE: To report a patient with a large gastrointestinal stromal tumor (GIST) who received multiple blood transfusions intraoperatively and developed a transfusion-related acute lung injury (TRALI). DESIGN: Case report. SETTING: Intensive care unit of a tertiary care hospital. PATIENT AND HISTORY: A 58-year-old man with GIST metastatic to the right lobe of the liver, treated with tyrosine kinase inhibitors, underwent a right hepatectomy requiring multiple transfusions. Prior to abdominal closure, he developed copious pulmonary secretions, hypoxemia, and hypotension. Chest radiograph revealed diffuse bilateral infiltrates. INTERVENTION: Volume resuscitation, vasopressors, high PEEP mechanical ventilation, paralysis, nitric oxide, steroids, rapid albumin infusion. MEASUREMENTS AND MAIN RESULTS: Extensive noncardiogenic pulmonary edema. After unsuccessful fluid resuscitation with crystalloid fluid, the patient's condition improved rapidly with human albumin boluses. No neurological deficit was detected despite prolonged hypoxemia. Acute renal failure required dialysis but with subsequent recovery. Patient was discharged home on postoperative day 19. CONCLUSION: Rapid infusion of albumin might be a rescue option in cases of severe TRALI with extensive pulmonary capillary leak during the acute phase.

Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury.

We show that transsynaptic apoptosis is induced in the superficial dorsal horn (laminas I-III) of the spinal cord by three distinct partial peripheral nerve lesions: spared nerve injury, chronic constriction, and spinal nerve ligation. Ongoing activity in primary afferents of the injured nerve and glutamatergic transmission cause a caspase-dependent degeneration of dorsal horn neurons that is slow in onset and persists for several weeks. Four weeks after spared nerve injury, the cumulative loss of dorsal horn neurons, determined by stereological analysis, is >20%. GABAergic inhibitory interneurons are among the neurons lost, and a marked decrease in inhibitory postsynaptic currents of lamina II neurons coincides with the induction of apoptosis. Blocking apoptosis with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD) prevents the loss of GABAergic interneurons and the reduction of inhibitory currents. Partial peripheral nerve injury results in pain-like behavioral changes characterized by hypersensitivity to tactile or cold stimuli. Treatment with zVAD, which has no intrinsic analgesic properties, attenuates this neuropathic pain-like syndrome. Preventing nerve injury-induced apoptosis of dorsal horn neurons by blocking caspase activity maintains inhibitory transmission in lamina II and reduces pain hypersensitivity.

Impact of menopausal status on the behavior of pancreatic cystic neoplasms in women.

PURPOSE: Pancreatic cystic neoplasms have predilections for occurring in young women, for containing "ovarian-like" stroma, and for expressing estrogen and progesterone receptors; these factors suggest a potentially important influence of the hormonal milieu on the biology of these tumors. Therefore, we examined the impact of menopausal status on the clinical features of pancreatic cystic neoplasms in women. METHODS: Seventy-six women with pancreatic cystic neoplasms treated at our institution from 1992 to 2003 were classified into 2 groups according to menopausal status based on the U.S. average menopausal age of 51 years: group I (premenopausal, ages 22-50; n = 36) and group II (postmenopausal, ages 51-80; n = 40). Chi-square and the 2-tailed t-tests compared categorical and continuous variables, respectively. Kaplan-Meier survival estimates were determined and compared with the log rank test. RESULTS: Abdominal pain at presentation occurred more commonly among group I than among group II patients (78% vs 48%, p < 0.05). Solid pseudopapillary tumors were more prevalent among group I than among group II patients (21% vs 3%, p = 0.02). CONCLUSIONS: The clinicopathologic features of pancreatic cystic neoplasms in premenopausal women are not significantly different from those in postmenopausal women. Menopausal status should not bias diagnostic and treatment algorithms for women with these neoplasms.

Control of basement membrane remodeling and epithelial branching morphogenesis in embryonic lung by Rho and cytoskeletal tension.

Local alterations in the mechanical compliance of the basement membrane that alter the level of isometric tension in the cell have been postulated to influence tissue morphogenesis. To explore whether cell tension contributes to tissue pattern formation in vivo, we modulated cytoskeletal force generation in embryonic mouse lung (embryonic days 12-14) rudiments using inhibitors of Rho-associated kinase (ROCK), myosin light chain kinase, myosin ATPase, and microfilament integrity, or a Rho stimulator (cytotoxic necrotizing factor-1). Tension inhibition resulted in loss of normal differentials in basement membrane thickness, inhibition of new terminal bud formation, and disorganization of epithelial growth patterns as well as disruption of capillary blood vessels. In contrast, increasing cell tension through Rho activation, as confirmed by quantitation of myosin light chain phosphorylation and immunohistocytochemical analysis of actin organization, accelerated lung branching and increase capillary elongation. These data suggest that changes in cytoskeletal tension mediated by Rho signaling through ROCK may play an important role in the establishment of the spatial differentials in cell growth and extracellular matrix remodeling that drive embryonic lung development.

Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn.

Primary afferent A-fiber stimulation normally evokes fast mono- or polysynaptic EPSCs of short duration. However, in the presence of the GABA(A) receptor antagonist bicuculline, repetitive, long lasting, polysynaptic EPSCs can be observed following the initial, fast response. A-fiber-induced ERK activation is also facilitated in the presence of bicuculline. The frequency of miniature EPSCs and the amplitude of the monosynaptic A-fiber-evoked EPSCs are not affected by bicuculline or the GABA(A) receptor agonist muscimol, suggesting that GABA(A) receptors located on somatodendritic sites of excitatory interneurons are critical for this action. Bicuculline-enhanced polysynaptic EPSCs are completely eliminated by NMDA receptor antagonists APV and ketamine, as was the augmented ERK activation. This NMDA receptor-dependent phenomenon may contribute to bicuculline-induced allodynia or hyperalgesia, as well as the hypersensitivity observed in neuropathic pain patients.

Menopausal effects on presentation, treatment, and survival of women with non-small cell lung cancer.

BACKGROUND: Small population studies have reported higher survival rates for women than men with non-small cell lung carcinoma (NSCLC). Because human NSCLC cells express estrogen receptors, we evaluated hormonally active and inactive women to identify biologically mediated differences. METHODS: A total of 14,676 US women with stage I through IV primary non-small cell lung cancer (NSCLC) from the 1992 to 1997 Surveillance, Epidemiology, and End Results database were grouped into two categories based on the average menopausal age of 51 years as defined by the American College of Obstetricians and Gynecologists: ages 31 to 50 premenopausal (n = 2,230, 15%) and ages 51 to 70 postmenopausal (n = 12,446, 85%). Extreme ages were excluded. Statistics were calculated with chi(2) or Mann-Whitney tests, Kaplan-Meier estimates with log-rank tests, and Cox proportional hazards models. RESULTS: Premenopausal women more commonly presented with advanced clinical stage, less favorable histology (adenocarcinoma), and poorly differentiated tumors, and more often underwent pneumonectomies. Surgery with curative intent was performed in 31% premenopausal and 33% postmenopausal women (p = 0.03). Overall survival for premenopausal and postmenopausal women was not significantly different (median 10 and 9 months, all stages; 70 and 71 months, stages I and II). Adjusting for significant covariates (stage, histology, size, grade, extent of surgery), postmenopausal women had higher lung-cancer-related deaths (hazard ratio, 1.14; 95% confidence interval, 1.03 to 1.27). CONCLUSIONS: Premenopausal women presented more often with advanced disease and underwent more extensive resection, yet had survival advantage after covariate adjustment. Additionally, postmenopausal women had a survival advantage compared with their male counterparts. Results suggest that estrogen exposure creates a milieu that may confer a protective effect through some yet unknown mechanisms that determine outcome of the neoplastic process and warrant further investigation.

Adenosine gates synaptic plasticity at hippocampal mossy fiber synapses.

The release properties of synapses in the central nervous system vary greatly, not only across anatomically distinct types of synapses but also among the same class of synapse. This variation manifests itself in large part by differences in the probability of transmitter release, which affects such activity-dependent presynaptic forms of plasticity as paired-pulse facilitation and frequency facilitation. This heterogeneity in presynaptic function reflects differences in the intrinsic properties of the synaptic terminal and the activation of presynaptic neurotransmitter receptors. Here we show that the unique presynaptic properties of the hippocampal mossy fiber synapse are largely imparted onto the synapse by the continuous local action of extracellular adenosine at presynaptic A1 adenosine receptors, which maintains a low basal probability of transmitter release.

Central sensitization and LTP: do pain and memory share similar mechanisms?

Synaptic plasticity is fundamental to many neurobiological functions, including memory and pain. Central sensitization refers to the increased synaptic efficacy established in somatosensory neurons in the dorsal horn of the spinal cord following intense peripheral noxious stimuli, tissue injury or nerve damage. This heightened synaptic transmission leads to a reduction in pain threshold, an amplification of pain responses and a spread of pain sensitivity to non-injured areas. In the cortex, LTP - a long-lasting highly localized increase in synaptic strength - is a synaptic substrate for memory and learning. Analysis of the molecular mechanisms underlying the generation and maintenance of central sensitization and LTP indicates that, although there are differences between the synaptic plasticity contributing to memory and pain, there are also striking similarities.

Implementing potentially better practices for improving family-centered care in neonatal intensive care units: successes and challenges.

OBJECTIVE: Multidisciplinary teams from 11 medical center neonatal intensive care units collaborated in a quality improvement project with a focus on family-centered care. METHODS: Through a process of self-analysis, literature review, benchmarking site visits, and expert consultation, 10 potentially better practice (PBP) areas were defined. Improvement activities in 4 of the 10 areas are given as examples of successes and challenges that individual centers encountered. The 4 areas are vision and philosophy, unit culture, family participation in care, and families as advisors. RESULTS: Centers were at different places for all of the PBPs at the beginning and throughout the collaboration. Seven centers developed or revised their vision or philosophy of care statements about family-centered care. Incorporating the vision and philosophy of care into performance appraisals, hiring of new personnel, and changing unit culture to a more family-centered practice were more challenging than developing the statements. Full parent participation in care requires unrestricted access to the neonatal intensive care unit. The shift from considering parents to be "visitors" to being partners in caring for their child was more difficult for centers with restricted visitation policies. All centers developed, expanded, or started plans for establishing family advisory councils. The experience of 2 centers is described. CONCLUSIONS: Family-centered care is more of a journey than a destination. Collaborating centers in this project found themselves at different places in that journey. Through perseverance in implementing the PBPs, all have moved further along the path.

Peripheral nerve injury alters excitatory synaptic transmission in lamina II of the rat dorsal horn.

Using the blind whole cell patch-clamp recording technique, we investigated peripheral nerve injury-induced changes in excitatory synaptic transmission to neurones in lamina II of the dorsal horn. Partial (i.e. chronic constriction injury (CCI) and spared nerve injury (SNI)) and complete (i.e. sciatic nerve transection (SNT)) peripheral nerve injury altered the mean threshold intensity for eliciting A fibre-mediated EPSCs in lamina II neurones. Following SNT and CCI, EPSC threshold was significantly decreased, but following SNI, EPSC threshold was increased (naive: 32 +/- 2 mu A, SNT: 22 +/- 2 mu A, CCI: 23 +/- 2 mu A, SNI: 49 +/- 4 mu A; P < 0.01, Student's unpaired t test). Despite this disparity between models, dorsal root compound action potential recordings revealed no significant difference in the conduction velocity or activation threshold of A beta and A delta fibres in naive, SNT, CCI and SNI rats. In addition to the changes in EPSC threshold, we also observed a shift in the distribution of EPSCs. In spinal cord slices from naive rats, polysynaptic A beta fibre-evoked EPSCs were observed in 24 % of lamina II neurones, monosynaptic A delta fibre EPSCs were observed in 34 % and polysynaptic A delta fibre EPSCs were observed in 7 %. Following SNT and CCI, the percentage of neurones with polysynaptic A beta fibre EPSCs increased to > or = 65 % of the sampled population, while the percentage of neurones with monosynaptic A delta fibre EPSCs decreased to < 10 %. The percentage of neurones with polysynaptic A delta fibre EPSCs was unchanged. In contrast, following SNI, A beta fibre EPSCs decreased in incidence while the percentage of neurones with polysynaptic A delta fibre EPSCs increased to 44 %. Similar to the other injury models, however, monosynaptic A delta fibre EPSCs decreased in frequency following SNI. Thus, excitatory synaptic transmission is subject to divergent plasticity in different peripheral nerve injury models, reflecting the complexity of responses to different forms of deafferentation.

Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord.

To clarify whether inhibitory transmission in the superficial dorsal horn of the spinal cord is reduced after peripheral nerve injury, we have studied synaptic transmission in lamina II neurons of an isolated adult rat spinal cord slice preparation after complete sciatic nerve transection (SNT), chronic constriction injury (CCI), or spared nerve injury (SNI). Fast excitatory transmission remains intact after all three types of nerve injury. In contrast, primary afferent-evoked IPSCs are substantially reduced in incidence, magnitude, and duration after the two partial nerve injuries, CCI and SNI, but not SNT. Pharmacologically isolated GABA(A) receptor-mediated IPSCs are decreased in the two partial nerve injury models compared with naive animals. An analysis of unitary IPSCs suggests that presynaptic GABA release is reduced after CCI and SNI. Partial nerve injury also decreases dorsal horn levels of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) 65 kDa ipsilateral to the injury and induces neuronal apoptosis, detected by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining in identified neurons. Both of these mechanisms could reduce presynaptic GABA levels and promote a functional loss of GABAergic transmission in the superficial dorsal horn.

Control of embryonic lung branching morphogenesis by the Rho activator, cytotoxic necrotizing factor 1.

BACKGROUND: Lung development is sensitive to physiological stresses, and its development may be impaired by physical distortion, as in patients with congenital diaphragmatic hernia. Yet, little is known about how mechanical forces can influence lung morphogenesis. Studies with cultured cells suggest that cytoskeletal tension may play a key role in growth control. Since the small GTPase Rho plays an important role in the control of cell tension generation, we carried out studies to test the hypothesis that changes in Rho-mediated cell tension may influence branching morphogenesis. METHODS: Embryonic lung buds from timed pregnant Swiss Webster mice were microdissected on Embryonic Day 12 (E12), and whole organs were cultured in serum-free medium in the presence of the Rho activator cytotoxic necrotizing factor 1 (CNF-1) for 48 h. Serial measurements of the degree of epithelial branch formation and tissue maturation were performed using light microscopy and computerized image analysis. RESULTS: At 48 h, embryonic lungs treated with 2 ng/ml CNF-1 increased their terminal bud count by 236 +/- 18% (P = 0.01) compared with 132 +/- 2% for untreated controls. However, dose-response experiments revealed biphasic behavior: at a higher dose of CNF-1 (200 ng/ml), bud number was actually decreased relative to controls (43 +/- 1%, P < 0.001). Histological analysis revealed that individual glands appeared to be more highly developed at low-dose CNF-1, whereas the high dose produced gland contraction. CONCLUSIONS: These data support a potential role for Rho and cytoskeletal tension in control of epithelial pattern formation during lung development.

5-HT(3) receptors mediate inflammation-induced unmasking of functional tachykinin responses in vitro.

Exogenously applied tachykinins produce no measurable electrophysiological responses in the somata of vagal afferent neurons [nodose ganglion neurons (NGNs)] isolated from naive guinea pigs. By contrast, after in vitro antigen challenge of nodose ganglia from guinea pigs immunized with chick ovalbumin, approximately 60% (53 of 89) of NGNs were depolarized an average of 13 +/- 1.2 mV by substance P (SP; 100 nM; n = 53). Receptor antagonists and enzyme inhibitors were utilized to screen a number of mast cell-derived mediators for their role in the uncovering or "unmasking" of functional tachykinin receptors after antigen challenge. Two chemically distinct 5-hydroxytryptamine-3-receptor antagonists significantly reduced the percentage of NGNs displaying depolarizing SP responses. Treatment with Y-25130 (1 or 10 microM) or tropisetron (1 microM) 15 min before and during antigen challenge reduced the percentage of SP-responsive neurons to approximately 20 and approximately 15% respectively. These results suggest that activation of 5-hydroxytryptamine-3 receptors plays an integral role in the unmasking of functional tachykinin receptors after specific antigen challenge of nodose ganglia. The mediator(s) underlying tachykinin-receptor unmasking in the remainder of the NGNs has yet to be characterized. However, it does not appear to be histamine, prostanoids, or peptidoleukotrienes.