Coding of odor stimulus features among secondary olfactory structures.

Sensory systems must represent stimuli in manners dependent upon a wealth of factors, including stimulus intensity and duration. One way the brain might handle these complex functions is to assign the tasks throughout distributed nodes, each contributing to information processing. We sought to explore this important aspect of sensory network function in the mammalian olfactory system, wherein the intensity and duration of odor exposure are critical contributors to odor perception. This is a quintessential model for exploring processing schemes given the distribution of odor information by olfactory bulb mitral and tufted cells into several anatomically distinct secondary processing stages, including the piriform cortex (PCX) and olfactory tubercle (OT), whose unique contributions to odor coding are unresolved. We explored the coding of PCX and OT neuron responses to odor intensity and duration. We found that both structures similarly partake in representing descending intensities of odors by reduced recruitment and modulation of neurons. Additionally, while neurons in the OT adapt to odor exposure, they display reduced capacity to adapt to either repeated presentations of odor or a single prolonged odor presentation compared with neurons in the PCX. These results provide insights into manners whereby secondary olfactory structures may, at least in some cases, uniquely represent stimulus features.

Encoding and representation of intranasal CO2 in the mouse olfactory cortex.

Intranasal trigeminal sensory input, often perceived as a burning, tingling, or stinging sensation, is well known to affect odor perception. While both anatomical and functional imaging data suggest that the influence of trigeminal stimuli on odor information processing may occur within the olfactory cortex, direct electrophysiological evidence for the encoding of trigeminal information at this level of processing is unavailable. Here, in agreement with human functional imaging studies, we found that 26% of neurons in the mouse piriform cortex (PCX) display modulation in firing to carbon dioxide (CO2), an odorless stimulant with known trigeminal capacity. Interestingly, CO2 was represented within the PCX by distinct temporal dynamics, differing from those evoked by odor. Experiments with ascending concentrations of isopentyl acetate, an odorant known to elicit both olfactory and trigeminal sensations, resulted in morphing of the temporal dynamics of stimulus-evoked responses. Whereas low concentrations of odorant evoked responses upon stimulus onset, high concentrations of odorant and/or CO2 often evoked responses structured to stimulus offset. These physiological experiments in mice suggest that PCX neurons possess the capacity to encode for stimulus modality (olfactory vs trigeminal) by differential patterns of firing. These data provide mechanistic insights into the influences of trigeminal information on odor processing and place constraints on models of olfactory-trigeminal sensory integration.

Trends in the Incidence of Spontaneous Subarachnoid Hemorrhages in the United States, 2007-2017.

BACKGROUND AND OBJECTIVE: To test the hypothesis that age-specific, sex-specific, and race-specific and ethnicity-specific incidence of nontraumatic subarachnoid hemorrhage (SAH) increased in the United States over the last decade. METHODS: In this retrospective cohort study, validated International Classification of Diseases codes were used to identify all new cases of SAH (n = 39,475) in the State Inpatients Databases of New York and Florida (2007-2017). SAH counts were combined with Census data to calculate incidence. Joinpoint regression was used to compute the annual percentage change (APC) in incidence and to compare trends over time between demographic subgroups. RESULTS: Across the study period, the average annual age-standardized/sex-standardized incidence of SAH in cases per 100,000 population was 11.4, but incidence was significantly higher in women (13.1) compared with that in men (9.6), p < 0.001. Incidence also increased with age in both sexes (men aged 20-44 years: 3.6; men aged 65 years or older: 22.0). Age-standardized and sex-standardized incidence was greater in Black patients (15.4) compared with that in non-Hispanic White (NHW) patients (9.9) and other races and ethnicities, p < 0.001. On joinpoint regression, incidence increased over time (APC 0.7%, p < 0.001), but most of this increase occurred in men aged 45-64 years (APC 1.1%, p = 0.006), men aged 65 years or older (APC 2.3%, p < 0.001), and women aged 65 years or older (APC 0.7%, p = 0.009). Incidence in women aged 20-44 years declined (APC -0.7%, p = 0.017), while those in other age/sex groups remained unchanged over time. Incidence increased in Black patients (APC 1.8%, p = 0.014), whereas that in Asian, Hispanic, and NHW patients did not change significantly over time. DISCUSSION: Nontraumatic SAH incidence in the United States increased over the last decade predominantly in middle-aged men and elderly men and women. Incidence is disproportionately higher and increasing in Black patients, whereas that in other races and ethnicities did not change significantly over time.

Persistence of intact retinal ganglion cell terminals after axonal transport loss in the DBA/2J mouse model of glaucoma.

Axonal transport defects are an early pathology occurring within the retinofugal projection of the DBA/2J mouse model of glaucoma. Retinal ganglion cell (RGC) axons and terminals are detectable after transport is affected, yet little is known about the condition of these structures. We examined the ultrastructure of the glaucomatous superior colliculus (SC) with three-dimensional serial block-face scanning electron microscopy to determine the distribution and morphology of retinal terminals in aged mice exhibiting varying levels of axonal transport integrity. After initial axonal transport failure, retinal terminal densities did not vary compared with either transport-intact or control tissue. Although retinal terminals lacked overt signs of neurodegeneration, transport-intact areas of glaucomatous SC exhibited larger retinal terminals and associated mitochondria. This likely indicates increased oxidative capacity and may be a compensatory response to the stressors that this projection is experiencing. Areas devoid of transported tracer label showed reduced mitochondrial volumes as well as decreased active zone number and surface area, suggesting that oxidative capacity and synapse strength are reduced as disease progresses but before degeneration of the synapse. Mitochondrial volume was a strong predictor of bouton size independent of pathology. These findings indicate that RGC axons retain connectivity after losing function early in the disease process, creating an important therapeutic opportunity for protection or restoration of vision in glaucoma. J. Comp. Neurol. 524:3503-3517, 2016. © 2016 Wiley Periodicals, Inc.

Validation of a Gyrolab™ assay for quantification of rituximab in human serum.

INTRODUCTION: Gyrolab™ technology presents a technology breakthrough for large molecule bioanalysis to support biologic drug development. The advantages of this innovative platform include fully automated nanoscale immunoassay capability, better assay reproducibility and data quality, small reagent and sample volumes, and rapid assay development and validation as a result of reduced run time. Although Gyrolab has been increasingly used in method development in discovery environment, few fully validated Gyrolab assays have been reported. Here we report a method validation of a Gyrolab assay to determine rituximab levels in human serum. METHODS: Rituximab is captured on a Bioaffy™ CD by a biotinylated rat anti-idiotypic monoclonal antibody against rituximab and detected by an Alexa Fluor®-labeled anti-human IgG antibody. Assay conditions were optimized to give required sensitivity and dynamic range. The assay validation was conducted according to the current industry standards for GLP-regulated immunoassays. RESULTS: The intrabatch precision and accuracy for the assay were determined using spiked human serum samples and shown to have a coefficient of variation (CV) of <11% with a mean bias <20%. The interbatch precision (CV) and absolute mean bias were both <12% with the total error <25%. Adequate spike recovery was demonstrated in serum samples of healthy individuals and solid tumor patients. The dilutional linearity test showed that the determined concentrations adjusted with various dilution factors had a linear relationship with the expected concentrations and that there was no hook effect. The method has been validated for the quantification of rituximab in human serum from 90 to 60,000 ng/mL with a minimum required dilution of 30. DISCUSSION: The Gyrolab assay was proved to be accurate, precise and selective, with a comparable sensitivity to the ELISA method, but provided an automated nanoscale assay with a significantly wider assay dynamic range for the determination of rituximab in human serum during pharmacokinetics/toxicokinetics studies.