Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Colonoscopy skills improvement training improves patient comfort during colonoscopy.

INTRODUCTION: We aimed to assess the effect of Colonoscopy Skills Improvement (CSI) training on patient comfort and sedation-related complications during colonoscopy. METHODS: This retrospective cohort study was performed on 19 endoscopists practicing in a Canadian tertiary care center who completed CSI training between October 2014 and May 2016. Data from 50 procedures immediately prior to, immediately after, and eight months following CSI training were included for each endoscopist. The primary outcome variable was intraprocedural comfort, and secondary outcomes included intraprocedural hypotension and hypoxia. Data were extracted from an electronic medical record and analyzed using SPSS version 20.0. Univariate analysis and stepwise multivariable logistic regression were performed to determine if there was an association between patient comfort and CSI training. Predictors of these outcomes including patient age, gender, sedation use and dosing, procedure completion, quality of bowel preparation, endoscopist experience, and specialty were included in the analysis. RESULTS: 2533 colonoscopies were included in the study. The mean dose of sedatives was reduced immediately following CSI training and at 8 months for both Fentanyl (75.4 mcg v. 67.8 mcg v. 65.9 mcg, p < 0.001) and Midazolam (2.57 mg v. 2.27 mg v. 2.19 mg, p < 0.001). The percentage of patients deemed to have a comfortable exam improved following endoscopist participation in CSI training and remained improved at 8 months (55.1% v. 70.2% v. 69.8%, p < 0.001). No significant change in rates of intraprocedural hypoxia or hypotension were noted following CSI training. CONCLUSION: CSI training is associated with improved patient comfort and reduced sedation requirements during colonoscopy.

Community dynamics and the lower airway microbiota in stable chronic obstructive pulmonary disease, smokers and healthy non-smokers.

RATIONALE: The role bacteria play in the progression of COPD has increasingly been highlighted in recent years. However, the microbial community complexity in the lower airways of patients with COPD is poorly characterised. OBJECTIVES: To compare the lower airway microbiota in patients with COPD, smokers and non-smokers. METHODS: Bronchial wash samples from adults with COPD (n=18), smokers with no airways disease (n=8) and healthy individuals (n=11) were analysed by extended-culture and culture-independent Illumina MiSeq sequencing. We determined aerobic and anaerobic microbiota load and evaluated differences in bacteria associated with the three cohorts. Culture-independent analysis was used to determine differences in microbiota between comparison groups including taxonomic richness, diversity, relative abundance, 'core' microbiota and co-occurrence. MEASUREMENT AND MAIN RESULTS: Extended-culture showed no difference in total load of aerobic and anaerobic bacteria between the three cohorts. Culture-independent analysis revealed that the prevalence of members of Pseudomonas spp. was greater in the lower airways of patients with COPD; however, the majority of the sequence reads for this taxa were attributed to three patients. Furthermore, members of Bacteroidetes, such as Prevotella spp., were observed to be greater in the 'healthy' comparison groups. Community diversity (α and ß) was significantly less in COPD compared with healthy groups. Co-occurrence of bacterial taxa and the observation of a putative 'core' community within the lower airways were also observed. CONCLUSIONS: Microbial community composition in the lower airways of patients with COPD is significantly different to that found in smokers and non-smokers, indicating that a component of the disease is associated with changes in microbiological status.

Induction of the inflammatory regulator A20 by gibberellic acid in airway epithelial cells.

BACKGROUND AND PURPOSE: NF-κB-driven inflammation is negatively regulated by the zinc finger protein A20. Gibberellic acid (GA3 ) is a plant-derived diterpenoid with documented anti-inflammatory activity, which is reported to induce A20-like zinc finger proteins in plants. Here, we sought to investigate the anti-inflammatory effect of GA3 in airway epithelial cells and determine if the anti-inflammatory action relates to A20 induction. EXPERIMENTAL APPROACH: Primary nasal epithelial cells and a human bronchial epithelial cell line (16HBE14o-) were used. Cells were pre-incubated with GA3 , stimulated with Pseudomonas aeruginosa LPS; IL-6 and IL-8 release, A20, NF-κB and IκBα expression were then evaluated. To determine if any observed anti-inflammatory effect occurred via an A20-dependent mechanism, A20 was silenced using siRNA. KEY RESULTS: Cells pre-incubated with GA3 had significantly increased levels of A20 mRNA (4 h) and protein (24 h), resulting in a significant reduction in IL-6 and IL-8 release. This effect was mediated via reduced IκBα degradation and reduced NF-κB (p65) expression. Furthermore, the anti-inflammatory action of GA3 was abolished in A20-silenced cells. CONCLUSIONS AND IMPLICATIONS: We showed that A20 induction by GA3 attenuates inflammation in airway epithelial cells, at least in part through its effect on NF-κB and IκBα. GA3 or gibberellin-derived derivatives could potentially be developed into anti-inflammatory drugs for the treatment of chronic inflammatory diseases associated with A20 dysfunction.

A selective antagonist of histamine H4 receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin-1.

BACKGROUND AND PURPOSE: Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H4 receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 (LC-1/annexin-A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators. EXPERIMENTAL APPROACH: Ovalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg.kg⁻¹) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage (BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2 , LTB4 and TNF-α were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured. KEY RESULTS: OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2 , LTB4 and TNF-α levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2 , LTB4 and TNF-α in BAL fluid. CONCLUSIONS AND IMPLICATIONS: Antigen-induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-α and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up-regulation.

Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology.

Cultured primary epithelial cells are used to examine inflammation in cystic fibrosis (CF). We describe a new human model system using cultured nasal brushings. Nasal brushings were obtained from 16 F508del homozygous patients and 11 healthy controls. Cells were resuspended in airway epithelial growth medium and seeded onto collagen-coated flasks and membranes for use in patch-clamp, ion transport, and mediator release assays. Viable cultures were obtained with a 75% success rate from subjects with CF and 100% from control subjects. Amiloride-sensitive epithelial Na channel current of similar size was present in both cell types while forskolin-activated CF transmembrane conductance regulator current was lacking in CF cells. In Ussing chambers, cells from CF patients responded to UTP but not to forskolin. Spontaneous and cytomix-stimulated IL-8 release was similar (stimulated 29,448 ± 9,025 pg/ml; control 16,336 ± 3,308 pg/ml CF; means ± SE). Thus nasal epithelial cells from patients with CF can be grown from nasal brushings and used in electrophysiological and mediator release studies in CF research.

Activation of alpha1 and alpha2 noradrenergic receptors exert opposing effects on excitability of main olfactory bulb granule cells.

The mammalian main olfactory bulb (MOB) receives a dense noradrenergic innervation from the pontine nucleus locus coeruleus that is important for neonatal odor preference learning and odor processing in mature animals. Modulation of GABAergic granule cells (GCs) is thought to play a key role in the net functional impact of norepinephrine (NE) release in the MOB, yet there are few direct studies of the influence of NE on these cells. In the present study we investigated noradrenergic modulation of GC excitability using electrophysiological approaches in rat MOB slices. A moderate concentration of NE (10 microM) and the alpha1 receptor agonist phenylephrine (10 microM) depolarized and increased spontaneous or current injection-evoked spiking in GCs. By contrast, low NE concentrations (0.1-1.0 microM) or the alpha2 receptor agonist clonidine (Clon, 10 microM) hyperpolarized and decreased the discharge of GCs. The effects of NE (10 microM) were blocked by antagonism of alpha1 and alpha2 receptors. Inhibitory effects of low NE concentrations were blocked or converted to excitatory responses by alpha2 receptor blockade, whereas excitatory effects of the moderate NE concentration were converted to inhibitory responses after alpha1 receptor blockade. NE (10 microM) and phenylephrine elicited inward currents that reversed near the potassium equilibrium potential. The effects of NE and phenylephrine were associated with increased membrane input resistance. Clonidine elicited an outward current associated with decreased membrane input resistance that reversed near the potassium equilibrium potential. These results indicate that alpha1 and alpha2 receptor activation exert opposing effects on GC excitability. Low concentrations of NE acting via alpha2 receptors suppress GC excitability, while higher concentrations of NE acting at alpha1 receptors increase GC excitability. These findings are consistent with recent findings that alpha1 and alpha2 receptor activation increase and decrease, respectively, GABAergic inhibition of mitral cells. The differential affinities of alpha1 and alpha2 noradrenergic receptor subtypes may allow for differential modulation of GABA release and olfactory processing as a function of the level of NE release, which in turn, is regulated by behavioral state.

The Biomarkers Consortium: practice and pitfalls of open-source precompetitive collaboration.

Precompetitive collaboration is a growing driver for innovation and increased productivity in biomedical science and drug development. The Biomarkers Consortium, a public-private platform for precompetitive collaboration specific to biomarkers, demonstrated that adiponectin has potential utility as a predictor of metabolic responses to peroxisome proliferator-activated receptor (PPAR) agonists in individuals with type 2 diabetes. Despite the challenges overcome by this project, the most important lesson learned is that cross-company precompetitive collaboration is a feasible robust approach to biomarker qualification.

Clinical phenotype of cystic fibrosis patients with the G551D mutation.

BACKGROUND: Data on whether the phenotype of cystic fibrosis (CF) patients with compound heterozygocity for G551D (Gly551Asp) differs from patients with F508del (Phe508del) homozygous mutations is divergent. AIM: We hypothesized that CF patients with the G551D mutation would have less severe disease than F508del homozygotes. DESIGN: We compared the clinical phenotype of adult patients with a G551D mutation with adult patients homozygous for F508del and those with the missense mutation R117H (Arg117His). Compound heterozygotes for the G551D and R117H were analysed separately. METHODS: Data were collected for 101 adult CF patients. Group 1-4 represents in order F508del homozygote patients (n = 61), those with the G551D mutation and a more severe mutation (n = 13), those with R117H mutation and a more severe mutation (n = 23) and also those compound for both the R117H and G551D mutations (n = 4). RESULTS: Our findings have shown that adult patients with the G551D mutation and a second severe mutation have a milder clinical phenotype than F508del homozygous adult patients. Higher FEV(1) and body mass index and less impaired glucose tolerance was demonstrated in the patients with G551D and R117H compared to F508del homozygotes. There was a reduced yearly rate of decline of FEV(1) (P < 0.05), infection with Pseudomonas aeruginosa along with reduced burden of care. Compound heterozygosity for G551D and R117H mutations was associated with normal spirometry, body mass index, no chronic infection and no symptoms. CONCLUSION: Mutations on different chromosomes are not independent of each other for the overall impact on the amount of functional CFTR. This study suggests that patients with the G551D mutation and a second severe mutation have a milder clinical phenotype than F508del homozygous patients, but the phenotype is not as mild as patients with the R117H mutation.

Utility of adiponectin as a biomarker predictive of glycemic efficacy is demonstrated by collaborative pooling of data from clinical trials conducted by multiple sponsors.

This study, conducted under the Metabolic Disorders Steering Committee of the Biomarkers Consortium (a public-private partnership managed by the Foundation for the National Institutes of Health (FNIH)), analyzed blinded data on 2,688 type 2 diabetes (T2D) patients from randomized clinical trials conducted by four pharmaceutical companies. An increase in the levels of adiponectin was observed after peroxisome proliferator-activated receptor (PPAR)-agonist treatment (P < 0.0001), but not after treatment with non-PPAR drugs. This increase correlated with decreases in levels of glucose, hemoglobin A(1c) (Hb(A1c)), hematocrit, and triglycerides, and increases in levels of blood urea nitrogen, creatinine, and high-density lipoprotein cholesterol (HDL-C). Early (6-8 weeks) increases in levels of adiponectin after treatment with PPAR agonists showed a negative correlation (r = -0.21, P < 0.0001) with subsequent changes in levels of Hb(A1c). Changes in adiponectin level did not appear to be associated with baseline level of Hb(A1c). Logistic regression demonstrated that an increase in the level of adiponectin predicts a decrease in the level of Hb(A1c). These analyses confirm previously demonstrated relationships between adiponectin levels and metabolic parameters and support the robust predictive utility of adiponectin across the spectrum of glucose tolerance. Cross-company precompetitive collaboration is a feasible and powerful approach to biomarker qualification.

Quality of life and inflammation in exacerbations of bronchiectasis.

Patients with bronchiectasis often have impaired quality of life (QoL), which deteriorates with exacerbations. The aim of this study was to investigate changes in QoL and how these were influenced by changes in airway physiology and inflammation in patients with bronchiectasis before and after resolution of an exacerbation. Sputum induction and a QoL questionnaire were undertaken on the first day, day 14, and 4 weeks after completion of intravenous antibiotics (day 42). Eighteen patients (12 female) were recruited, median (IQ range) age of 54 (47-60) years. There was a trend towards an improvement in lung function from visit 1 to visit 2, but this was not statistically significant. C-reactive protein (CRP) [mean (SEM)] reduced between visit 1 and visit 2 [55.4 (21.5) vs 9.4 (3.1) mg/L, P = 0.03] but did not increase significantly on visit 3 [44.4 (32.9) mg/L, P = 0.27]. The median (interquartile range) sputum cell count (x10(6) cells/g of sputum) decreased from visit 1 to visit 2 [21.6 (11.8-37.6)-13.3 (6.7-22.9) x 10(6) cells/g, respectively, P = 0.008] and increased from visit 2 to visit 3 [26.3 (14.1-33.6) x 10(6) cells/g, P = 0.03]. All soluble markers of inflammation significantly reduced from visit 1 to visit 2 but increased on visit 3 with the exception of TNF-alpha. Regarding QoL, three of the four domains (dyspnoea, emotional, mastery) significantly improved from visit 1 to visit 2 but did not change between visit 2 and visit 3. The improvements in QoL scores could not be explained by the improvements in lung function or inflammatory markers.

A randomized controlled trial of a health promotion education programme for people with multiple sclerosis.

OBJECTIVE: To evaluate the effectiveness of a health promotion education programme for people with multiple sclerosis (the OPTIMISE programme) in terms of increasing the level of health-promoting activity undertaken, improving self-efficacy and enhancing quality of life. DESIGN: A randomized controlled single blinded trial. Non-parametric analysis was undertaken to test for significant differences between treatment and control groups change scores. SUBJECTS AND SETTING: Sixty-two adults (32 treatment and 30 control subjects) with multiple sclerosis of any type, Expanded Disability Status Scale (EDSS) 1-7. INTERVENTION: An eight-week multidisciplinary outpatient health promotion education programme aimed at increasing knowledge, skills and confidence in undertaking health promotion activities. OUTCOME MEASURES: Health Promoting Lifestyle Profile, Self-Rated Abilities for Health Practices Scale and the Short Form 36 Item Health Survey. RESULTS: Following completion of the programme, treatment subjects had significantly higher levels of health promotion activity undertaken (P < 0.01) and self-efficacy for health promotion activities (P < 0.01). These benefits were sustained for at least three months after the programme ceased. Certain domains of quality of life also improved in treatment subjects more than controls (physical P = 0.03, mental health and general health P = 0.01), although only mental health and general health showed further improvement at three months. Participants provided positive feedback regarding the usefulness of the intervention and demonstrated observable changes to their health promotion behaviours. CONCLUSIONS: The OPTIMISE programme produced significant changes in health-promoting behaviours.

Children with stable asthma have reduced airway matrix metalloproteinase-9 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio.

BACKGROUND: Childhood asthma is characterized by inflammation of the airways. Structural changes of the airway wall may also be seen in some children early in the course of the disease. Matrix metalloproteinases (MMPs) are key mediators in the metabolism of the extracellular matrix (ECM). OBJECTIVE: To investigate the balance of MMP-8, MMP-9 and tissue inhibitor of metalloproteinases (TIMP)-1 in the airways of children with asthma. METHODS: One hundred and twenty-four children undergoing elective surgical procedures also underwent non-bronchoscopic bronchoalveolar lavage (BAL). MMP-8, MMP-9 and TIMP-1 were measured by ELISA. RESULTS: There was a significant reduction in MMP-9 in atopic asthmatic children (n=31) compared with normal children (n=30) [median difference: 0.57 ng/mL (95% confidence interval: 0.18-1.1 ng/mL)]. The ratio of MMP-9 to TIMP-1 was also reduced in asthmatic children. Levels of all three proteins were significantly correlated to each other and to the relative proportions of particular inflammatory cells in BAL fluid (BALF). Both MMP-8 and MMP-9 were moderately strongly correlated to the percentage neutrophil count (r=0.40 and 0.47, respectively, P<0.001). CONCLUSIONS: An imbalance of MMPs and their inhibitors occurs in children with well-controlled asthma, which may indicate early derangement of the metabolism of the ECM.

Neutrophils and eosinophils: clinical implications of their appearance, presence and disappearance in asthma and COPD.

Asthma and chronic obstructive pulmonary disease (COPD) are common chronic disorders. Traditionally, asthma has been associated with an eosinophilic inflammation and COPD with neutrophilic inflammation. In this review we will highlight the maturation, recruitment, activation, action and apoptosis of these cells. In addition we will focus on the evidence for their presence in disease and suggest potential new therapeutic interventions.

Neutrophil cell death, activation and bacterial infection in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterised by chronic endobronchial bacterial infection and neutrophil mediated inflammation. Neutrophil apoptosis is essential for the resolution of inflammation. This study assessed the relationship between levels of neutrophil apoptosis and sputum microbiology in matched clinically stable patients with CF. METHODS: Sputum was induced from 34 patients (nine with no Gram negative infection, 10 colonised with Pseudomonas aeruginosa, 10 with Burkholderia cenocepacia, and five with other infections). Apoptotic neutrophils measured by flow cytometric Annexin V/propidium iodide staining and morphology were similar in all groups. RESULTS: Patients infected with P aeruginosa or B cenocepacia had a significantly lower percentage of viable neutrophils in the sputum than those with no Gram negative infection (Kruskal-Wallis p = 0.01, median (interquartile range (IQR)) 14.2% (9.4-21.6), 15.8% (12.3-19.5), and 48.4% (23.0-66.4); p = 0.003 and p = 0.002, respectively). They also had significantly higher levels of secondary necrotic granulocytes in sputum than patients with no Gram negative infection (Kruskal-Wallis p<0.0001, median (IQR) 55.5% (48.4-64.5), 50.4% (44.6-61.9), and 24.8% (14.4-30.5); p<0.0001 and p<0.0001, respectively). Neutrophils (x 10(6)/g sputum) in P aeruginosa infected patients (Kruskal-Wallis p = 0.05, median (IQR) 6.3 (3.5-12.7)) and B cenocepacia infected patients (5.7 (1.5-14.5)) were significantly higher than in the group with no Gram negative infection (0.5 (0.5-4.3), p = 0.03 and 0.04, respectively). CONCLUSION: These results suggest that cell death and clearance may be altered in patients with CF colonised with P aeruginosa and B cenocepacia compared with those with no Gram negative infection.

A brainstem substrate for analgesia elicited by intraoral sucrose.

Previous studies demonstrated that nursing or intraoral infusion of certain components of mother's milk (e.g. sugars and fats) produces calming and opiate receptor-dependent analgesia in newborn rats and humans. However, the neural circuitry underlying such analgesia is unknown. The aim of the present study was to specify the central pathways by which taste stimuli engage neural antinociceptive mechanisms. For this purpose, midcollicular transactions were used to investigate the role of the forebrain in analgesia elicited by intraoral infusion of 0.2 M sucrose in neonatal rats. Sucrose-induced analgesia persisted, and was enhanced, following midcollicular transection, indicating that it did not require neural circuits confined to the forebrain. Fos immunohistochemistry was used to identify brainstem neurons activated by a brief (90 s) intraoral infusion of a small volume (90 microl, 0.2M) of sucrose or a salt solution (0.1 M ammonium chloride) in 10-day-old rat pups. Compared with control groups (intact, cannula, distilled water), both sucrose and ammonium chloride induced Fos expression in the rostral nucleus tractus solitarius, the first relay in the ascending gustatory pathway. Sucrose also elicited Fos expression in several brainstem areas associated with centrally mediated analgesia, including the periaqueductal gray and the nucleus raphe magnus. Taken together, these findings demonstrate that analgesia elicited by intraoral sucrose does not require involvement of the forebrain. Intraoral sucrose activates neurons in the periaqueductal gray and nucleus raphe magnus, two key brainstem sites critically involved in descending pain modulation.

Properties of external plexiform layer interneurons in mouse olfactory bulb slices.

In the external plexiform layer (EPL) of the main olfactory bulb, apical dendrites of inhibitory granule cells form large numbers of synapses with mitral and tufted (M/T) cells, which regulate the spread of activity along the M/T cell dendrites. The EPL also contains intrinsic interneurons, the functions of which are unknown. In the present study, recordings were obtained from cell bodies in the EPL of mouse olfactory bulb slices. Biocytin-filling confirmed that the recorded cells included interneurons, tufted cells, and astrocytes. The interneurons had fine, varicose dendrites, and those located superficially bridged the EPL space below several adjacent glomeruli. Interneuron activity was characterized by high frequency spontaneous excitatory postsynaptic potential/currents that were blocked by the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and largely eliminated by the voltage-sensitive Na+ channel blocker, tetrodotoxin. Interneuron activity differed markedly from that of tufted cells, which usually exhibited spontaneous action potential bursts. The interneurons produced few action potentials spontaneously, but often produced them in response to depolarization and/or olfactory nerve (ON) stimulation. The responses to depolarization resembled responses of late- and fast-spiking interneurons found in other cortical regions. The latency and variability of the ON-evoked responses were indicative of polysynaptic input. Interneurons expressing green fluorescent protein under control of the mouse glutamic acid decarboxylase 65 promoter exhibited identical properties, providing evidence that the EPL interneurons are GABAergic. Together, these results suggest that EPL interneurons are excited by M/T cells via AMPA/kainate receptors and may in turn inhibit M/T cells within spatial domains that are topographically related to several adjacent glomeruli.