Development of a novel in vitro system for nasal drug delivery development

There is currently, no ideal system for studying nasal drug delivery in vitro. The existing techniques such as the Ussing chamber and cell culture all have major disadvantages. Most importantly, none of the existing techniques accurately represent the interior of the nasal cavity, with its airflow and humidity; neither do they allow the investigation of solid dosage forms.The work in this thesis represents the development of an in vitro model system in which the interior characteristics of the nasal cavity are closely represented, and solid or minimal volume dosage forms can be investigated. The complete nasal chamber consists of two sections: a lower tissue, viability chamber and an upper nasal chamber. The lower tissue viability chamber has been shown, using existing tissue viability monitoring techniques, to maintain the viability of a number of epithelial tissues, including porcine and rabbit nasal tissue, and rat ileal and Payers' patch tissue. The complete chamber including the upper nasal chamber has been shown to provide tissue viability for porcine and rabbit nasal tissue above that available using the existing Ussing chamber techniques. Adaptation of the complete system, and the development of the necessary experimental protocols that allow aerosol particle-sizing, together with videography, has shown that the new factors investigated, humidity and airflow, have a measurable effect on the delivered dose from a typical nasal pump. Similarly, adaptation of the chamber to fit under a confocal microscope, and the development of the necessary protocols has shown the effect of surface and size on the penetration of microparticulate materials into nasal epithelial tissues. The system developed in this thesis has been shown to be flexible, in allowing the development of the confocal and particle-sizing systems. For future nasal drug delivery studies, the ability to measure such factors as the size of the delivered system in the nasal cavity, the depth of penetration of the formulation into the tissue are essential. Additionally, to have access to other data such as that obtained from drug transport in the same system, and to have the tissue available for histological examination represents a significant advance in the usefulness of such an in vitro technique for nasal delivery

Ultrasmall silica nanoparticles directly ligate the T cell receptor complex.

The impact of ultrasmall nanoparticles (<10-nm diameter) on the immune system is poorly understood. Recently, ultrasmall silica nanoparticles (USSN), which have gained increasing attention for therapeutic applications, were shown to stimulate T lymphocytes directly and at relatively low-exposure doses. Delineating underlying mechanisms and associated cell signaling will hasten therapeutic translation and is reported herein. Using competitive binding assays and molecular modeling, we established that the T cell receptor (TCR):CD3 complex is required for USSN-induced T cell activation, and that direct receptor complex-particle interactions are permitted both sterically and electrostatically. Activation is not limited to αβ TCR-bearing T cells since those with γδ TCR showed similar responses, implying that USSN mediate their effect by binding to extracellular domains of the flanking CD3 regions of the TCR complex. We confirmed that USSN initiated the signaling pathway immediately downstream of the TCR with rapid phosphorylation of both ζ-chain-associated protein 70 and linker for activation of T cells protein. However, T cell proliferation or IL-2 secretion were only triggered by USSN when costimulatory anti-CD28 or phorbate esters were present, demonstrating that the specific impact of USSN is in initiation of the primary, nuclear factor of activated T cells-pathway signaling from the TCR complex. Hence, we have established that USSN are partial agonists for the TCR complex because of induction of the primary T cell activation signal. Their ability to bind the TCR complex rapidly, and then to dissolve into benign orthosilicic acid, makes them an appealing option for therapies targeted at transient TCR:CD3 receptor binding.These studies were supported by grants from the UK Medical Research Council (Grant number MR/R005699/1) and the Natural Sciences and Engineering Research Council of Canada, as well as through sponsorship from HS Pharmaceuticals LLC

A perspective on emerging automotive safety applications, derived from lessons learned through participation in the DARPA Grand Challenges

This paper reports on various aspects of the Intelligent Vehicle Systems (IVS) team's involvement in the recent 2007 DARPA Urban Challenge, wherein our platform, the autonomous “XAV-250,'' competed as one of the 11 finalists qualifying for the event. We provide a candid discussion of the hardware and software design process that led to our team's entry, along with lessons learned at this event and derived from participation in the two previous Grand Challenges. In addition, we give an overview of our vision-, radar-, and LIDAR-based perceptual sensing suite, its fusion with a military-grade inertial navigation package, and the map-based control and planning architectures used leading up to and during the event. The underlying theme of this article is to elucidate how the development of future automotive safety systems can potentially be accelerated by tackling the technological challenges of autonomous ground vehicle robotics. Of interest, we will discuss how a production manufacturing mindset imposes a unique set of constraints upon approaching the problem and how this worked for and against us, given the very compressed timeline of the contests. © 2008 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61244/1/20264_ftp.pd

Patterns of Incubation Behavior in Northern Bobwhites (\u3ci\u3eColinus virginianus\u3c/i\u3e)

Patterns of incubation and nesting behavior for many species of birds, especially those with cryptic nests, have been difficult to obtain due to logistical and technological limitations. As a result, little is known about the daily attendance rhythms and behavioral patterns of many species, including the Northern Bobwhite (Colinus virginianus), despite this species being one of the most studied birds in the world. Incubation represents parental investment in offspring, and a multitude of factors may affect investment behaviors, including reproductive ecology, sex and age of parent, habitat quality, clutch age, and timing in the nesting season. Most Northern Bobwhite nests are incubated by a single adult, most often by females, but also by some males. We assessed the nest attendance patterns and parental investment in bob-white clutches (n 118) using continuous near-infrared video of nests being incubated by male or female bobwhites. We found that incubating parents took 0 –3 recesses per day. A single recess was most common for 87% of nest-days, and most of these were during mid-day to late afternoon (12:00 19:00). Mean total daily recess time was 182 min (95% CI: 98–264) for nests that hatched and 224 min (95% CI: 140–308) for nests that failed. We observed no difference between sexes in the number or length of recesses taken, but females initiated recess later in the day (median start time 15:00) than males (median start time 14:00). We found that nest recess length decreased as the clutch got older and increased as the nesting season progressed. Video surveillance systems proved to be a use-ful tool for observing and quantifying patterns of incubation behavior in a ground-nesting species with cryptic nests

Patterns of Incubation Behavior in Northern Bobwhites (\u3ci\u3eColinus virginianus\u3c/i\u3e)

Patterns of incubation and nesting behavior for many species of birds, especially those with cryptic nests, have been difficult to obtain due to logistical and technological limitations. As a result, little is known about the daily attendance rhythms and behavioral patterns of many species, including the Northern Bobwhite (Colinus virginianus), despite this species being one of the most studied birds in the world. Incubation represents parental investment in offspring, and a multitude of factors may affect investment behaviors, including reproductive ecology, sex and age of parent, habitat quality, clutch age, and timing in the nesting season. Most Northern Bobwhite nests are incubated by a single adult, most often by females, but also by some males. We assessed the nest attendance patterns and parental investment in bob-white clutches (n 118) using continuous near-infrared video of nests being incubated by male or female bobwhites. We found that incubating parents took 0 –3 recesses per day. A single recess was most common for 87% of nest-days, and most of these were during mid-day to late afternoon (12:00 19:00). Mean total daily recess time was 182 min (95% CI: 98–264) for nests that hatched and 224 min (95% CI: 140–308) for nests that failed. We observed no difference between sexes in the number or length of recesses taken, but females initiated recess later in the day (median start time 15:00) than males (median start time 14:00). We found that nest recess length decreased as the clutch got older and increased as the nesting season progressed. Video surveillance systems proved to be a use-ful tool for observing and quantifying patterns of incubation behavior in a ground-nesting species with cryptic nests

Early surgical intervention among patients with acute central cord syndrome is not associated with higher mortality and morbidity

Background: Conflicting reports exist regarding mortality and morbidity of early surgical decompression in the setting of acute central cord syndrome (ACS) in multisystem trauma despite evidence of improved neurological outcomes. Consequently, optimal decompression timing in ACS in multisystem trauma patients remains controversial. This study aims to determine the association between early surgery for acute traumatic central cord and all-cause mortality among multisystem trauma patients in the National Trauma Data Bank (NTDB) using propensity score matching. Methods: We used the NTDB (years 2011-2014) to perform a retrospective cohort study, which included patients \u3e18 years, with ACS (identified using ICD-9 coding). Collected patient data included demographics, surgery timing (≤24 hours, \u3e24 hours), injury mechanism, Charlson comorbidity index (CCI), injury severity score (ISS), serious adverse events (SAE). Logistic regression and propensity matching were used to investigate the relationship between surgery timing and subsequent inpatient mortality. Results: We identified 2,379 traumatic ACS patients. This group was 79.3% male with an average age of 56.3±15.2. They had an average ISS of 19.5±9.0 and mortality rate of 3.0% (n=72). A total of 731 (30.7%) patients underwent surgery for ACS within 24 hours. Univariate analysis did not show a significantly higher mortality rate in the early versus late surgery groups (3.8% Conclusions: Early surgical intervention does not appear to be associated with increased mortality among ACS patients unlike previously suggested. We theorize that survival noted within the NTDB is confounded by factors including existing comorbidities and multisystem trauma, rather than surgical timing. Delaying definitive surgical care may predispose patients to worsened greater neurological morbidity

Evolutionary biology for the 21st century

New theoretical and conceptual frameworks are required for evolutionary biology to capitalize on the wealth of data now becoming available from the study of genomes, phenotypes, and organisms - including humans - in their natural environments.Molecular and Cellular BiologyOrganismic and Evolutionary Biolog

Genetic screening in sporadic ALS and FTD.

The increasing complexity of the genetic landscape in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) presents a significant resource and physician training challenge. At least 10% of those diagnosed with ALS or FTD are known to carry an autosomal dominant genetic mutation. There is no consensus on what constitutes a positive family history, and ascertainment is unreliable for many reasons. However, symptomatic individuals often wish to understand as much as possible about the cause of their disease, and to share this knowledge with their family. While the right of an individual not to know is a key aspect of patient autonomy, and despite the absence of definitive therapy, many newly diagnosed individuals are likely to elect for genetic testing if offered. It is incumbent on the practitioner to ensure that they are adequately informed, counselled and supported in this decision