510 research outputs found
Effect of Acute Bilateral Vagotomy on Tissue-Specific Inflammation in a Murine Model of Systemic Lupus Erythematosus
No full textEffect of Acute Bilateral Vagotomy on Tissue-Specific Inflammation in a Murine Model of Systemic Lupus Erythematosus
Shyam Vedantam, Grace S Pham, Keisa W Mathis
Purpose: Chronic inflammation has been implicated in the pathogenesis of hypertension. We use a model of systemic lupus erythematosus (SLE) to study this relationship since SLE is a chronic autoimmune inflammatory disorder with a high prevalence of renal injury and hypertension. SLE is also associated with diminished autonomic (vagal) tone, and this implicates impaired neuroendocrine/neuroimmune mechanisms. One example is the classic hypothalamic-pituitary-adrenal (HPA) axis, which can be activated by the afferent vagus nerve and result in cortisol production and anti-inflammatory effects. Another example is the cholinergic anti-inflammatory pathway, an endogenous vagus nerve-to-spleen pathway that reduces inflammation upon stimulation. It is thought that both of these mechanisms are dysregulated and promote chronic inflammation in SLE. To confirm the importance of the vagus nerve in regulating inflammation though these mechanisms, we performed chronic unilateral vagotomy in SLE mice and determined that this paradoxically decreased inflammatory markers in the spleen and the kidney. We hypothesized that the other vagus nerve compensated and upregulated an anti-inflammatory response and that total vagotomy would exacerbate splenic and renal inflammation.
Methods: In the current study, anesthetized female SLE (NZBWF1) and control (NZW) mice (35 weeks of age; n=3 mice/group) underwent bilateral vagotomy and were euthanized 3 hours later, followed by tissue harvest.
Results: Spleen tumor necrosis factor (TNF)-a (measured by Western blot and normalized to total protein) was increased in SLE mice compared to controls (4.0e6 ± 2.2e6 vs. 1.5e6 ± 3.3e5; P=NS). Acute bilateral vagotomy exacerbated this inflammation in SLE mice (5.1e6 ± 2.5e6) and controls (3.2e6 ± 6.8e5). Renal cortical TNF-a was not different in SLE and control mice (7.4e5 ± 1.6e5 vs. 6.9e5 ± 4.8e4); however, acute bilateral vagotomy exacerbated TNF-a in SLE mice (1.3e6 ± 7.2e4 vs) and controls (1.2e6 ±6.5e5).
Conclusions: These findings suggest that the vagus nerve and vagally-mediated anti-inflammatory mechanisms like the HPA axis and the cholinergic anti-inflammatory pathway are critical in controlling inflammation in SLE. Future studies involving chronic bilateral vagotomy in SLE mice are necessary to confirm our hypotheses
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The Role of EspH and Host Cell Proteins in Enteropathogenic Escherichia Coli-Induced Cell Death and Virulence
No full textEnteropathogenic Escherichia coli (EPEC) is a leading cause of infantile diarrhea, particularly in developing countries. EPEC belongs to the attaching and effacing (A/E) family of pathogens and harbors a type III secretion system (T3SS) that delivers virulence proteins directly into host epithelial cells. These proteins alter host structure and function, likely facilitating pathogenesis. We recently demonstrated that EspH, an EPEC secreted protein, is a critical virulence factor and that mutant strains lacking espH are impaired for pathogenesis. EspH induces host cell death through activation of caspases and mitochondrial fission. We hypothesizes that a wide range of host proteins are implicated in this cell death phenotype. Quantitation of host cell death during EPEC infection using siRNA-mediated knockdown of individual host cell proteins supports this hypothesis. A broad group of host protein knockdowns displayed altered host cell death during infection. The goal of my studies is to identify the host pathway(s) altered during EspH-induced epithelial cell death and, eventually, to establish the significance of this pathway in EPEC virulence.Release after 30-Apr-2024Originally set to release after 10-May-2020; contacted by author on 03-May-2019 to extend embargo through 30-Apr-2024, Kimberl
Rate of recurrence following stereotactic aspiration of colloid cysts of the third ventricle
No full textBACKGROUND:
The rate of recurrence following stereotactic aspiration of colloid cysts is not defined in the literature.
AIMS:
To study the long-term imaging and clinical outcome in patients who had stereotactic aspiration of colloid cysts of the third ventricle.
METHODS:
Between 1987 and 1994, computerized tomography-guided stereotactic aspiration was attempted in 26 consecutive patients with colloid cysts of the third ventricle.
RESULTS:
There was no mortality or permanent morbidity. A complete aspiration of the cyst was possible in 17 patients, a partial aspiration of the cyst was achieved in 6 and the aspiration failed in 3 patients. On long-term follow-up, symptomatic recurrence was noted in 5/6 patients after partial aspiration and 4/17 patients after complete aspiration (mean follow-up 84.8 months). Kaplan-Meier analysis revealed that after complete aspiration of the cyst, median time to recurrence on imaging is 42 months (95% CI 23.0-60.9 months) but median time to symptomatic recurrence is much later at 184 months (95% CI 88.2-279.7 months).
CONCLUSIONS:
Stereotactic aspiration of colloid cysts remains a valid surgical option as complete aspiration leads to a good long-term outcome in several patients. Partial aspiration of the cyst should be followed by excision of the cyst, due to the high rate of symptomatic recurrence. However, periodic follow-up imaging is mandatory even after complete aspiration as delayed recurrences are possible
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Comparative Phenotypic and Genomics Approaches Provide Insight into the Tripartite Symbiosis of Xenorhabdus bovienii with Steinernema Nematode and Lepidopteran Insect Hosts
No full textNematodes are highly diverse animals capable of interacting with almost every other form of life on Earth from general trophic interactions to intimate and persistent symbiotic associations. Much of their recognition originates from their various parasitic lifestyles. From an agricultural standpoint, plant parasitic nematodes are widely known for the destruction they can cause to crop plants, such as the case of the root-knot nematode Meloidogyne incognita, or livestock animals, like the Trichinella spiralis, which infects pigs and other animals. From a human health perspective, nematodes can cause many debilitating diseases, for example Wuchereria bancrofti, which is a causative agent of lymphatic filariasis or elephantiasis. However, not all parasitic nematodes have bad implications for human health. For instance, the diverse interactions of insect parasitic nematodes can be used to our benefit. Many of these species have been considered as biological control alternatives to different insect pests that wreak havoc on human, animal, and plant health. There still remain many questions surrounding their evolution, ecology, and physiological capabilities. Many of these taxa are hard to cultivate in the lab due to their complex and intimate lifestyles. Entomopathogenic nematodes (EPNs) are of great interest in agriculture because they vector insect pathogenic bacteria, which are capable of causing death to an insect host within 48 hours post-infection. Much of the molecular underpinnings in this system still remain to be discovered, from understanding the basic ability of these two organisms to associate with one another to genetically engineering more robust and host specific pathogens for application in the field. The focus of the research presented herein is on Steinernematidae nematodes and their bacterial symbionts. Specifically, it focused on the relationship between Xenorhabdus bovienii and its Steinernema hosts. Bioassays were designed to investigate insect virulence of X. bovienii alone in two Lepidoptera insect species with known differential susceptibility to Steinernema-Xenorhabdus pairs. A comparative genomic analysis was performed to compare different Xenorhabdus bovienii strains with observed variation in insect virulence. Results from this analysis demonstrated that virulent strains possess a type VI secretion system (T6SS) locus that is completely absent in strains with attenuated virulence. Bacterial competition assays between T6SS+ and T6SS- strains suggest this locus is involved in bacterial competition. Additionally, symbiont preference assays were carried out to investigate whether Steinernema hosts are able to discern between virulent and attenuated X. bovienii strains. Results from these assays revealed that Steinernema nematodes are able to distinguish between cognate and non-cognate X. bovienii symbionts, giving preference to virulent strains over those with attenuated virulence. Altogether these results provide further evidence that supports the notion that symbiont-switching events have occurred over the Steinernema-Xenorhabdus co-evolutionary history. Specifically, the competitive virulence of certain X. bovienii strains may have conferred them the ability to be selected by different Steinernema hosts, therefore contributing to the success of the nematode-bacterium partnership in being pathogenic to diverse insect hosts.Release 12-Jan-201
Hundreds of variants clustered in genomic loci and biological pathways affect human height
No full textMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits(1), but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait(2,3). The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways
A nonstandard finite difference scheme for a strain-gradient theory
No full text10.1007/s00466-004-0624-7Computational Mechanics355369-375CMME
Constitutive equations for rate-dependent pseudoelastic behaviour of shape memory alloys
No full text10.1088/0964-1726/15/5/003Smart Materials and Structures1551172-1178SMST
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Prevalence and Genetics of Survival of Salmonella in Oysters
No full textSalmonella enterica is a leading cause of food-borne gastrointestinal disease worldwide. A survey conducted in 2002-2003 showed that oysters may contain Salmonella and thus may also be a source of salmonellosis. Since oysters are commonly consumed raw, no amount of food safety education will prevent consumers from ingesting a possibly infectious dose from Salmonella contaminated oysters. The research in this dissertation employed a combination of traditional culture techniques as well as genomics-based molecular applications to explore Salmonella infection in oysters and the subsequent risk to consumers of raw oysters. A year-long survey of oysters served on the half-shell in local restaurants determined that overall 1.2% of oysters were contaminated with Salmonella. Oysters containing Salmonella were found in 7 of the 8 months surveyed and 7 of the 8 restaurants served contaminated oysters. Six different serovars were isolated, but one strain of S. Newport, as determined by matching pulsed field gel electrophoresis patterns, represented 43% of the positive samples. Interestingly, this is the same strain that was predominantly isolated in the earlier survey of oysters and was also resistant to at least 7 different antimicrobials. The remainder of this dissertation work was an exploration of why this particular strain is seen so often in oyster infections. A custom microarray was used to perform a transposon site hybridization (TraSH) assay to identify genes that are necessary for S. Newport survival in the oyster. In this way, a negative selection was able to determine the genes that were necessary for S. Newport to survive in oysters. A subset of the genes identified by TraSH was selected and site-directed mutagenesis was performed to knock those genes out of LAJ160311. Oysters were infected with those mutant strains to test for their ability to survive in oysters and thereby determine the role of those individual genes in pathogenesis. The conclusions of the TraSH assay were that virulence factors that are essential for survival of Salmonella in mammalian models, particularly the type three secretion systems, may not be important in the oyster model. Motility provided by flagella was identified as a major virulence factor in oyster colonization by S. Newport
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