A proposed association between subjective nonpulsatile tinnitus and migraine.

Objective: Tinnitus is defined as the perception of sound in the absence of an external source. We propose the hypothesis that migraine can cause exacerbation of tinnitus in some patients. Methods: English literature from PubMed has been reviewed. Results: Studies have reported a high prevalence of cochlear symptoms in patients with migraine headaches and up to 45% of tinnitus patients have been shown to concomitantly suffer from migraine. Both conditions are thought to stem from central nervous system disturbances, involving disruption of the auditory and trigeminal nerve pathways. One proposed mechanism of this association is the modulation of sound sensitivity by trigeminal nerve activation of the auditory cortex during migraine attacks, resulting in tinnitus fluctuation in some patients. Increased brain and inner ear vascular permeability resulting from trigeminal nerve inflammation, can also cause observed headache and auditory symptoms. Tinnitus and migraine also share a number of symptom triggers including stress, sleep disturbances, and dietary factors. These shared features may help explain promising results of migraine therapies for the treatment of tinnitus. Conclusion: Given the complex association between tinnitus and migraine, further investigation is needed to identify the underlying mechanisms and determine the optimal treatment strategies for managing migraine-related tinnitus patients.

Quantification of structural heterogeneity in H&E stained clear cell renal cell carcinoma using refractive index tomography.

Clear cell renal cell carcinoma (ccRCC) is a common histopathological subtype of renal cancer and is notorious for its poor prognosis. Its accurate diagnosis by histopathology, which relies on manual microscopic inspection of stained slides, is challenging. Here, we present a correlative approach to utilize stained images and refractive index (RI) tomography and demonstrate quantitative assessments of the structural heterogeneities of ccRCC slides obtained from human patients. Machine-learning-assisted segmentation of nuclei and cytoplasm enabled the quantification at the subcellular level. Compared to benign regions, malignant regions exhibited a considerable increase in structural heterogeneities. The results demonstrate that RI tomography provides quantitative information in synergy with stained images on the structural heterogeneities in ccRCC.

Evaluating the predictive value of comorbidity indices in pituitary surgery: a mixed-effects modeling study using the Nationwide Readmissions Database.

OBJECTIVE: Although pituitary adenomas (PAs) are common intracranial tumors, literature evaluating the utility of comorbidity indices for predicting postoperative complications in patients undergoing pituitary surgery remains limited, thereby hindering the development of complex models that aim to identify high-risk patient populations. We utilized comparative modeling strategies to evaluate the predictive validity of various comorbidity indices and combinations thereof in predicting key pituitary surgery outcomes. METHODS: The Nationwide Readmissions Database was used to identify patients who underwent pituitary tumor operations (n = 19,653) in 2016-2017. Patient frailty was assessed using the Johns Hopkins Adjusted Clinical Groups (ACG) System. The Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI) were calculated for each patient. Five sets of generalized linear mixed-effects models were developed, using as the primary predictors 1) frailty, 2) CCI, 3) ECI, 4) frailty + CCI, or 5) frailty + ECI. Complications of interest investigated included inpatient mortality, nonroutine discharge (e.g., to locations other than home), length of stay (LOS) within the top quartile (Q1), cost within Q1, and 1-year readmission rates. RESULTS: Postoperative mortality occurred in 73 patients (0.4%), 1-year readmission was reported in 2994 patients (15.2%), and nonroutine discharge occurred in 2176 patients (11.1%). The mean adjusted all-payer cost for the procedure was USD $25,553.85 ± $26,518.91 (Q1 $28,261.20), and the mean LOS was 4.8 ± 7.4 days (Q1 5.0 days). The model using frailty + ECI as the primary predictor consistently outperformed other models, with statistically significant p values as determined by comparing areas under the curve (AUCs) for most complications. For prediction of mortality, however, the frailty + ECI model (AUC 0.831) was not better than the ECI model alone (AUC 0.831; p = 0.95). For prediction of readmission, the frailty + ECI model (AUC 0.617) was not better than the frailty model alone (AUC 0.606; p = 0.10) or the frailty + CCI model (AUC 0.610; p = 0.29). CONCLUSIONS: This investigation is to the authors' knowledge the first to implement mixed-effects modeling to study the utility of common comorbidity indices in a large, nationwide cohort of patients undergoing pituitary surgery. Knowledge gained from these models may help neurosurgeons identify high-risk patients who require additional clinical attention or resource utilization prior to surgical planning.

Long-term outcomes in sinonasal squamous cell carcinoma arising from inverted papilloma: Systematic review.

Long-term survival and recurrence patterns of squamous cell carcinoma arising from inverted papilloma (IP-SCC) have not been thoroughly investigated. Four electronic databases were searched and primary studies describing overall survival (OS), recurrence, and mean time to recurrence of patients with IP-SCC were included for review. Our search yielded 662 studies. The 28 studies selected for inclusion identified 663 patients with IP-SCC. In 596 patients with reported T classification, 439 (73.7%) were T3/T4 on presentation. Of the 650 participants with recurrence data (local, regional, and distant), 155 (23.8%) experienced a recurrence, with an aggregate mean time-to-recurrence of 24.3 months. In 565 patients with 5-year OS rates, the aggregate 5-year OS was 62%. Based on the literature to date, IP-SCC is associated with a 5-year OS rate of 62%. 23.8% of patients experienced recurrence at a mean time of 24.3 months, suggesting the need for long-term surveillance.

What Factors Lead to Racial Disparities in Outcomes After Total Knee Arthroplasty?

Total knee arthroplasty (TKA) is one of the most commonly performed, major elective surgeries in the USA. African American TKA patients on average experience worse clinical outcomes than whites, including lower improvements in patient-reported outcomes and higher rates of complications, hospital readmissions, and reoperations. The mechanisms leading to these racial health disparities are unclear, but likely involve patient, provider, healthcare system, and societal factors. Lower physical and mental health at baseline, lower social support, provider bias, lower rates of health insurance coverage, higher utilization of lower quality hospitals, and systemic racism may contribute to the inferior outcomes that African Americans experience. Limited evidence suggests that improving the quality of surgical care can offset these factors and lead to a reduction in outcome disparities.

Predictors of Postoperative Nausea and Vomiting After Endoscopic Skull Base Surgery.

OBJECTIVES/HYPOTHESIS: The objective of this study is to evaluate the impact of patient and surgical factors, including approach and reconstruction type, on postoperative nausea and vomiting episodes following endoscopic skull base surgery. STUDY DESIGN: Retrospective review. METHODS: We performed a retrospective chart review from July 2018 to August 2020 of 99 consecutive patients undergoing endoscopic skull base surgery at a tertiary academic skull base surgery program. All patients were treated with a standardized postoperative protocol consisting of scheduled ondansetron, along with promethazine and scopolamine for breakthrough nausea and vomiting episodes. Cumulative nausea and vomiting episodes throughout hospital stay were recorded for each patient. RESULTS: Of the 99 patients identified, the mean number of nausea and vomiting episodes per patient were 0.4 ± 1.2 and 0.3 ± 0.7, respectively. Female sex (ß = .65, P = .034) and extended surgical approach (ß = .90, P = .027) were associated with increased risk for postoperative nausea. Furthermore, female sex (ß = .44, P = .018), cavernous sinus dissection (ß = .52, P = .002), and extended approach (ß = .79, P = .025) significantly increased odds of postoperative vomiting episodes. There was no association between total operative time or total postoperative opioid dose and nausea and vomiting episodes (all Ps > .05). Neither increased nausea nor vomiting episodes significantly increased odds of prolonged hospitalization (P = .105 and .164, respectively). CONCLUSION: This report highlights novel risk factors for patients undergoing endoscopic skull base surgery. Upfront standing antiemetic therapy may be considered when treating patients with independent predictors of postoperative nausea and vomiting, including female sex, cavernous sinus dissection, and extended surgical approach. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:761-768, 2022.

Label-free monitoring of 3D cortical neuronal growth in vitro using optical diffraction tomography.

The highly complex central nervous systems of mammals are often studied using three-dimensional (3D) in vitro primary neuronal cultures. A coupled confocal microscopy and immunofluorescence labeling are widely utilized for visualizing the 3D structures of neurons. However, this requires fixation of the neurons and is not suitable for monitoring an identical sample at multiple time points. Thus, we propose a label-free monitoring method for 3D neuronal growth based on refractive index tomograms obtained by optical diffraction tomography. The 3D morphology of the neurons was clearly visualized, and the developmental processes of neurite outgrowth in 3D spaces were analyzed for individual neurons.

Migraine Features in Patients with Persistent Postural-Perceptual Dizziness.

OBJECTIVES: To evaluate the presence of migraine features in patients with persistent postural-perceptual dizziness (PPPD). METHODS: In a retrospective survey study, consecutive patients presenting to a tertiary care neurotology clinic during an 18-month period were given questionnaires about headache and dizziness symptoms. The survey responses plus history and examination of the patient were used to diagnose patients with PPPD. The prevalence of migraine headache, vestibular migraine (VM), and migraine characteristics was evaluated. RESULTS: In total, 36 subjects with PPPD were included in the study. The mean age of the subjects was 56 ± 16 years with a female (72%) predominance. A total of 19 (53%) patients met the International Classification of Headache Disorders criteria for migraine headache, and 6 of those (17%) met the criteria for definite VM. Of the patients who did not meet full migraine headache criteria, 6 (17%) patients met 4 of 5 criteria, and 5 (14%) patients met 3 of 5 criteria. There was no significant difference between PPPD patients who fulfilled full migraine headache criteria and those who did not in sensitivity to light, sound, smells, weather changes, feelings of mental fog/confusion, and sinus pain/facial pressure. CONCLUSIONS: This study demonstrates that a majority of patients with PPPD fulfill the criteria for migraine headache. A large proportion of PPPD patients who do not meet the full criteria for migraine headache still meet a majority of the migraine headache criteria. This suggests an association between the 2 conditions. PPPD may be a part of the spectrum of otologic migraine, where migraine manifests as otologic symptoms.

Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy.

We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.

Online Ratings and Perceptions of Pediatric Otolaryngologists.

OBJECTIVE/HYPOTHESIS: To assess and characterize online ratings and comments on pediatric otolaryngologists and determine factors that correlate with higher ratings. STUDY DESIGN: Online database analysis. METHODS: All American Society of Pediatric Otolaryngology (ASPO) members were queried on Healthgrades, Vitals, RateMDs, and Yelp for their online ratings and comments as of June 2020. Ratings were normalized for comparison on a five-point Likert scale. All comments were categorized based on context and positive or negative quality. RESULTS: Of the 561 ASPO members, 489 (87%) were rated on at least one online platform. Of those rated, 410 (84%) were on Healthgrades, 429 (88%) on Vitals, 236 (48%) on RateMDs, and 72 (15%) on Yelp. Across all platforms, the average overall rating was 4.13 ± 0.03 (range, 1.00-5.00). We found significant positive correlations between overall ratings and specific ratings (P < .001) on all individual topics. In addition, the majority of all narrative comments were related to perceived physician bedside manner and clinical outcome, with negative comments correlating negatively with overall score (P < .05). Time spent with the physician was the only category in which both positive and negative comments showed significant correlation with the overall physician rating (P = .016 and P = .017, respectively). Attending a top-ranked medical school or residency program did not correlate with higher or lower ratings. CONCLUSIONS: Online ratings and comments for pediatric otolaryngologists are largely influenced by patient and parent perceptions of physician competence, comforting bedside manner, and office and time management. LEVEL OF EVIDENCE: NA Laryngoscope, 131:2356-2360, 2021.

Minimally Invasive Image-Guided Gut Transport Function Measurement Probe.

Introduction: Diseases such as celiac disease, environmental enteric dysfunction, infectious gastroenteritis, type II diabetes and inflammatory bowel disease are associated with increased gut permeability. Dual sugar absorption tests, such as the lactulose to rhamnose ratio (L:R) test, are the current standard for measuring gut permeability. Although easy to administer in adults, the L:R test has a number of drawbacks. These include an inability to assess for spatial heterogeneity in gut permeability that may distinguish different disease severity or pathology, additional sample collection for immunoassays, and challenges in carrying out the test in certain populations such as infants and small children. Here, we demonstrate a minimally invasive probe for real-time localized gut permeability evaluation through gut potential difference (GPD) measurement. Materials and Methods: The probe has an outer diameter of 1.2 mm diameter and can be deployed in the gut of unsedated subjects via a transnasal introduction tube (TNIT) that is akin to an intestinal feeding tube. The GPD probe consists of an Ag/AgCl electrode, an optical probe and a perfusion channel all housed within a transparent sheath. Lactated Ringer's (LR) solution is pumped through the perfusion channel to provide ionic contact between the electrodes and the gut lining. The optical probe captures non-scanning (M-mode) OCT images to confirm electrode contact with the gut lining. A separate skin patch probe is placed over an abraded skin area to provide reference for the GPD measurements. Swine studies were conducted to validate the GPD probe. GPD in the duodenum was modulated by perfusing 45 ml of 45 mM glucose. Results: GPD values of -13.1 ± 2.8 mV were measured in the duodenum across four swine studies. The change in GPD in the duodenum with the addition of glucose was -10.5 ± 2.4 mV (p < 0.001). M-mode OCT images provided electrode-tissue contact information, which was vital in ascertaining the probe's proximity to the gut mucosa. Conclusion: We developed and demonstrated a minimally invasive method for investigating gastrointestinal permeability consisting of an image guided GPD probe that can be used in unsedated subjects.

Migraine Features in Patients With Recurrent Benign Paroxysmal Positional Vertigo.

OBJECTIVES: To identify migraine features present in a cohort of patients with recurrent benign paroxysmal positional vertigo (BPPV). METHODS: Patients presenting with recurrent BPPV were surveyed. Recurrent BPPV was defined as three episodes or greater in 6 months before presentation, with resolution of symptoms after Epley maneuver. Current or past migraine headache (MH) diagnosis was made according to the International Headache Society guidelines. RESULTS: Fifty-eight patients with recurrent BPPV with a mean age of 53.8 ±â€Š17.4 years were included. Half (29 patients) fulfilled criteria for MH and half (29 patients) did not meet the criteria for MH (non-MH). No statistically significant difference was found in a majority of migraine-related symptoms between the MH and non-MH cohorts with recurrent BPPV. History of migraine medication usage (p = 0.008), presence of a weekly headache (p = 0.01), and duration of dizziness after positional vertigo (p = 0.01) were the only variables that were different on multivariate analysis between the MH and non-MH cohorts. CONCLUSIONS: Half of recurrent BPPV patients suffer from migraine headaches. The other half presented with migraine-related symptoms, but do not meet criteria for MH. The high comorbidity of MH in our recurrent BPPV cohort as well as the absence of a statistically significant difference in a majority of migraine-related features among patients who did and did not fulfill criteria for MH may suggest that recurrent BPPV has a relationship with migraine. Recurrent BPPV may potentially be a manifestation of migraine in the inner ear, which we term otologic migraine including cochlear, vestibular, or cochleovestibular symptoms.

The association of age, body mass index, and frailty with vestibular schwannoma surgical morbidity.

OBJECTIVE: To evaluate whether increased body mass index (BMI), age, or frailty influence vestibular schwannoma (VS) short-term surgical morbidity. METHODS: The 2005-2017 National Surgical Quality Improvement Program database was queried for patients with VS undergoing surgical resection. Age was stratified according to age <50, 50-64, and ≥65, while BMI was stratified based on a threshold of 30. Frailty score (0-5) was indicated based on functional status, diabetes, chronic obstructive pulmonary disease, congestive heart failure, and hypertension. RESULTS: A total of 1405 patients were included consisting of 56.7 % females with a mean age of 50.7 ±â€¯13.8 years and mean BMI of 29.4 ±â€¯6.6. Patients <50 (n = 604), 50-64 (n = 578), and ≥65 (n = 223), had different duration of surgery (428 ±â€¯173 vs. 392 ±â€¯149 vs. 387 ±â€¯154 min; p < 0.001) and 30-day mortality rates (0.7 % vs. 0% vs. 1.8 %; p = 0.01). However, post-operative length of stay (LOS) (p = 0.16), readmission (p = 0.08), reoperation (p = 0.54), and complication rates were similar. Post-operative myocardial infarction (p = 0.03) and wound infection (p = 0.02) were more commonly observed in the obese cohort (BMI≥30) but readmission (p = 0.18), reoperation (p = 0.44), and complication rates were similar to those with BMI<30. Severely obese patients (BMI≥35) also had higher rates of deep vein thrombosis (p = 0.004). Frailty score 0 (n=921), 1 (n=375), and 2-4 (n=109) was associated with LOS (4.7±3.5 vs. 5.3 ±â€¯4.1 vs. 6.7 ±â€¯6.6 days, p < 0.001) and prolonged intubation rates (1.0 % vs. 2.4 % vs. 3.7 %; p = 0.03). CONCLUSIONS: Increased age, BMI, and frailty among VS patients were associated with different post-operative complication rates, operation time, or LOS. Knowledge of these can optimize care for at-risk patients.

Three-dimensional label-free imaging and quantification of migrating cells during wound healing.

The wound-healing assay is a simple but effective tool for studying collective cell migration (CCM) that is widely used in biophysical studies and high-throughput screening. However, conventional imaging and analysis methods only address two-dimensional (2D) properties in a wound healing assay, such as gap closure rate. This is unfortunate because biological cells are complex 3D structures, and their dynamics provide significant information about cell physiology. Here, we presented 3D label-free imaging for wound healing assays and investigated the 3D dynamics of CCM using optical diffraction tomography. High-resolution subcellular structures as well as their collective dynamics were imaged and analyzed quantitatively.

Different dietary fibre sources and risks of colorectal cancer and adenoma: a dose-response meta-analysis of prospective studies.

Dietary fibre is believed to provide important health benefits including protection from colorectal cancer. However, the evidence on the relationships with different dietary fibre sources is mixed and little is known about which fibre source provides the greatest benefits. We conducted a dose-response meta-analysis of prospective cohorts to summarise the relationships of different fibre sources with colorectal cancer and adenoma risks. Analyses were restricted to publications that reported all fibre sources (cereals, vegetables, fruits, legumes) to increase comparability between results. PubMed and Embase were searched through August 2018 to identify relevant studies. The summary relative risks (RR) and 95 % CI were estimated using a random-effects model. This analysis included a total of ten prospective studies. The summary RR of colorectal cancer associated with each 10 g/d increase in fibre intake were 0·91 (95 % CI 0·82, 1·00; I2 = 0 %) for cereal fibre, 0·95 (95 % CI 0·87, 1·03, I2 = 0 %) for vegetable fibre, 0·91 (95 % CI 0·78, 1·06, I2 = 43 %) for fruit fibre and 0·84 (95 % CI 0·63, 1·13, I2 = 45 %) for legume fibre. For cereal fibre, the association with colorectal cancer risk remained statistically significant after adjustment for folate intake (RR 0·89, 95 % CI 0·80, 0·99, I2 = 2 %). For vegetable and fruit fibres, the dose-response curve suggested evidence of non-linearity. All fibre sources were inversely associated with incident adenoma (per 10 g/d increase: RR 0·81 (95 % CI 0·54, 1·21) cereals, 0·84 (95 % CI 0·71, 0·98) for vegetables, 0·78 (95 % CI 0·65, 0·93) for fruits) but not associated with recurrent adenoma. Our data suggest that, although all fibre sources may provide some benefits, the evidence for colorectal cancer prevention is strongest for fibre from cereals/grains.

Coffee Intake and Obesity: A Meta-Analysis.

Many studies have explored the relationship between coffee-one of the most commonly consumed beverages today-and obesity. Despite inconsistent results, the relationship has not been systematically summarized. Thus, we conducted a meta-analysis by compiling data from 12 epidemiologic studies identified from PubMed and Embase through February 2019. The included studies assessed obesity by body mass index (BMI, a measure of overall adiposity) or waist circumference (WC, a measure of central adiposity); analyzed the measure as a continuous outcome or binary outcome. Using random effects model, weighted mean difference (WMD) and 95% confidence interval (CI) were obtained for continuous outcomes; summary relative risk (RR) and 95% CI for the highest vs. lowest categories of coffee intake were estimated for binary outcome. For BMI, WMD was -0.08 (95% CI -0.14, -0.02); RR was 1.49 (95% CI 0.97, 2.29). For WC, WMD was -0.27 (95% CI -0.51, -0.02) and RR was 1.07 (95% CI 0.84, 1.36). In subgroup analysis by sex, evidence for an inverse association was more evident in men, specifically for continuous outcome, with WMD -0.05 (95% CI -0.09, -0.02) for BMI and -0.21 (95% CI -0.35, -0.08) for WC. Our meta-analysis suggests that higher coffee intake might be modestly associated with reduced adiposity, particularly in men.

Nonadherence to Insulin Therapy Detected by Bluetooth-Enabled Pen Cap Is Associated With Poor Glycemic Control.

OBJECTIVE: To objectively evaluate adherence to timing and dosing of insulin by using Bluetooth pen caps and examine factors related to adherence. RESEARCH DESIGN AND METHODS: Bluetooth-enabled insulin pen caps were used in younger (ages 18-35 years) and older (ages ≥65 years) adults on two or more insulin injections per day. RESULTS: We evaluated 75 participants with diabetes, 42 younger (29 ± 4 years) and 33 older (73 ± 7 years). Nonadherence was found in 24% of bolus (Apidra) doses and 36% of basal (Lantus) doses. We divided participants into tertiles on the basis of overall adherence, with the most adherent tertile having 85% dose adherence compared with 49% in the least adherent tertile (P < 0.001). Participants in the most adherent tertile had better glycemic control than those in the least adherent tertile (7.7 ± 1.1% [61 ± 12 mmol/mol] vs. 8.6 ± 1.5% [70 ± 16.4 mmol/mol], P < 0.03). CONCLUSIONS: Nonadherence to insulin dosing and timing can be objectively assessed by Bluetooth pen caps and is associated with poor glycemic control.

The long tail and rare disease research: the impact of next-generation sequencing for rare Mendelian disorders.

There are an estimated 6000-8000 rare Mendelian diseases that collectively affect 30 million individuals in the United States. The low incidence and prevalence of these diseases present significant challenges to improving diagnostics and treatments. Next-generation sequencing (NGS) technologies have revolutionized research of rare diseases. This article will first comment on the effectiveness of NGS through the lens of long-tailed economics. We then provide an overview of recent developments and challenges of NGS-based research on rare diseases. As the quality of NGS studies improve and the cost of sequencing decreases, NGS will continue to make a significant impact on the study of rare diseases moving forward.

Inactivation of norovirus and surrogates by natural phytochemicals and bioactive substances.

Human norovirus is the leading cause of sporadic gastroenteritis, which is responsible for more than 90% of all nonbacterial gastroenteritis outbreaks. While norovirus infections typically cause mild and self-limiting symptoms lasting 24-48 h, chronic persistent infections can cause severe symptoms. Although recent advances have been made in understanding the molecular characteristics of norovirus infection, no norovirus-specific antiviral drugs, or vaccines are available. Conventional intervention methods used to inactivate norovirus, such as treatment with disinfecting agents (e.g. ethanol, hypochlorite, and quaternary ammonium formulations), have shown a lack of efficacy against human norovirus when they are applied to foods and in food preparation processes. Therefore, alternative antiviral or inactivating agents such as phytochemicals have received attention as potential norovirus inhibitors due to their relatively low toxicity and lack of side effects, which allows them to be prepared as food-safe formulations. Evidence from studies using viral surrogates suggests that numerous phytochemicals and foods containing flavonoids and polyphenols have anti-norovirus activity, and future studies will be necessary to confirm the effectiveness of such compounds against human norovirus and the molecular mechanisms through which they produce antiviral effects.

The mGluR7 allosteric agonist AMN082 produces antidepressant-like effects by modulating glutamatergic signaling.

Currently prescribed antidepressants affect the reuptake and/or metabolism of biogenic amines. Unfortunately for patients, these treatments require several weeks to produce significant symptom remission. However, recently it has been found that ketamine, a dissociative anesthetic agent that noncompetitively antagonizes NMDA (N-Methyl-d-aspartic acid) receptors, has rapid antidepressant effects at sub-anesthetic doses in clinically depressed patients. These findings indicate that modulation of the glutamatergic system could be an efficient way to achieve antidepressant activity. For this reason, other mechanisms influencing glutamatergic functioning have gained interest. For example, the metabotropic glutamate receptor 7 (mGluR7) allosteric agonist AMN082 (N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride) has been shown to be effective in the forced swim and tail-suspension test, behavioral assays sensitive to antidepressants. Here we extend the characterization of AMN082 by demonstrating its effects on differential reinforcement of low rates of responding (DRL)-30, another assay sensitive to antidepressants. Furthermore, we show the engagement of glutamatergic signaling by demonstrating the ability of the selective AMPA (2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid) receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione) to reverse the effects of AMN082 in the tail suspension test. In contrast, NBQX failed to reverse the effects of imipramine in the same behavioral test. Finally, we report that behaviorally efficacious doses of AMN082 modulate phosphorylation of AMPA and NMDA receptor subunits in the hippocampus. These results suggest that the antidepressant-like effects of AMN082 are, at least in part, due to modulation of AMPA and NMDA receptor activity. Therefore, our findings confirm the hypothesis that mGluR7 could represent a novel target for treating depression.