Agency, Equality, and Antidiscrimination Law

The Supreme Court increasingly has interpreted the Equal Protection Clause as a mandate for the state to treat citizens as if they were equal-as a limitation on the state\u27s ability to draw distinctions on the basis of characteristics such as race and, to a lesser extent, gender. In the context of race, the Court has struck down not only race-specific policies designed to harm the historically oppressed, but race conscious policies designed to foster racial equality. Although in theory the Court has left open the possibility that benign uses of race may be constitutional under some set of facts, in practice it has yet to identify such a policy since it adopted strict scrutiny across the board. In its equal protection analysis of gender, the Court has also moved toward a stricter level of scrutiny, calling into question the possibility of benign uses of gender as well. As the Supreme Court narrowed the scope of benign race-based categories permitted by the Constitution, political forces have launched attacks on affirmative action policies at both the state and federal levels. Some commentators, perhaps a minority, have argued that the Equal Protection Clause should be read to require the use of race-conscious policies when necessary to eradicate or remedy the most serious consequences of racial inequality. Others have argued that such policies, though not required, should be permitted when duly adopted by the majority of the populace to promote the interests of an historically oppressed minority. Still others, including now a majority of the Supreme Court, take the view that the Constitution forbids virtually all explicit uses of race by the state. In this Essay, we do not enter this debate directly. Rather, we attempt to explore the reasons behind the increasing acceptance of a norm of color-blindness-both politically and legally-and locate those reasons within a particular liberal conception of the limited, neutral state. We then attempt to demonstrate that the movement toward an increasingly strict view of discrimination as simply color consciousness has not been limited to the equal protection context

ADMA: A key player in the relationship between vascular dysfunction and inflammation in atherosclerosis

Atherosclerosis is a chronic cardiovascular disease which increases risk of major cardiovascular events including myocardial infarction and stroke. Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) have long been recognised as a hallmark of cardiovascular disease and are associated with cardiovascular risk factors including hypertension, obesity and hypertriglyceridemia. In this review, we discuss the clinical literature that link ADMA concentrations to increased risk of the development of atherosclerosis. The formation of atherosclerotic lesions relies on the interplay between vascular dysfunction, leading to endothelial activation and the accumulation of inflammatory cells, particularly macrophages, within the vessel wall. Here, we review the mechanisms through which elevated ADMA contributes to endothelial dysfunction, activation and reactive oxygen species (ROS) production; how ADMA may affect vascular smooth muscle phenotype; and finally whether ADMA plays a regulatory role in the inflammatory processes occurring within the vessel wall

Identification of co-regulated transcripts affecting male body size in Drosophila

Factor analysis is an analytic approach that describes the covariation among a set of genes through the estimation of 'factors', which may be, for example, transcription factors, microRNAs (miRNAs), and so on, by which the genes are co-regulated. Factor analysis gives a direct mechanism by which to relate gene networks to complex traits. Using simulated data, we found that factor analysis clearly identifies the number and structure of factors and outperforms hierarchical cluster analysis. Noise genes, genes that are not correlated with any factor, can be distinguished even when factor structure is complex. Applied to body size in Drosophila simulans, an evolutionarily important complex trait, a factor was directly associated with body size

Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: Impact of a “Top‐Down” approach to intestinal fibrosis in mice

Background: The natural history of Crohn's disease follows a path of progression from an inflammatory to a fibrostenosing disease, with most patients requiring surgical resection of fibrotic strictures. Potent antiinflammatory therapies reduce inflammation but do not appear to alter the natural history of intestinal fibrosis. The aim of this study was to determine the relationship between intestinal inflammation and fibrogenesis and the impact of a very early “top‐down” interventional approach on fibrosis in vivo. Methods: In this study we removed the inflammatory stimulus from the Salmonella typhimurium mouse model of intestinal fibrosis by eradicating the S. typhimurium infection with levofloxacin at sequential timepoints during the infection. We evaluated the effect of this elimination of the inflammatory stimulus on the natural history of inflammation and fibrosis as determined by gross pathology, histopathology, mRNA expression, and protein expression. Results: Fibrogenesis is preceded by inflammation. Delayed eradication of the inflammatory stimulus by antibiotic treatment represses inflammation without preventing fibrosis. Early intervention significantly ameliorates but does not completely prevent subsequent fibrosis. Conclusions: This study demonstrates that intestinal fibrosis develops despite removal of an inflammatory stimulus and elimination of inflammation. Early intervention ameliorates but does not abolish subsequent fibrosis, suggesting that fibrosis, once initiated, is self‐propagating, suggesting that a very early top‐down interventional approach may have the most impact on fibrostenosing disease. (Inflamm Bowel Dis 2012;)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90367/1/21812_ftp.pd

Transcriptional and pathway analysis in the hypothalamus of newly hatched chicks during fasting and delayed feeding

<p>Abstract</p> <p>Background</p> <p>The hypothalamus plays a central role in regulating appetite and metabolism. However, the gene networks within the hypothalamus that regulate feed intake and metabolism, and the effects of fasting on those pathways are not completely understood in any species. The present experiment evaluated global hypothalamic gene expression in newly hatched chicks using microarray analysis to elucidate genes and pathways regulated by feeding, fasting, and delayed feeding. Ten groups of chicks were sampled over four days post-hatch, including fed, fasted, and 48 h fasted followed by access to feed for 4 h, 24 h, and 48 h. Hypothalamic samples were collected for microarray analysis (n = 4). Expression patterns of selected genes were confirmed by quantitative real-time PCR. Pathway analysis of the microarray results predicted a network of genes involved in neuropeptide or neurotransmitter signaling. To confirm the functionality of this predicted gene network, hypothalamic neurons from fed and fasted chicks were isolated and cultured in the presence of neuropeptide Y, somatostatin, α-melanocyte stimulating hormone, norepinephrine, and L-phospho-serine. Results confirmed functional relationships among members of the predicted gene network. Moreover, the effects observed were dependant upon the nutritional state of the animals (fed <it>vs</it>. fasted).</p> <p>Results</p> <p>Differences in gene expression (≥ 1.6 fold) were detected in 1,272 genes between treatments, and of those, 119 genes were significantly (P < 0.05) different. Pathway Miner analysis revealed that six genes (<it>SSTR5</it>, <it>NPY5R</it>, <it>POMC</it>, <it>ADRB2</it>, <it>GRM8</it>, and <it>RLN3</it>) were associated within a gene network. <it>In vitro </it>experiments with primary hypothalamic neurons confirmed that receptor agonists involved in this network regulated expression of other genes in the predicted network, and this regulation within the network was influenced by the nutritional status and age of the chick.</p> <p>Conclusions</p> <p>Microarray analysis of the hypothalamus during different nutritional states revealed that many genes are differentially regulated. We found that functional interactions exist among six differentially regulated genes associated within a putative gene network from this experiment. Considering that <it>POMC</it>, an important gene in controlling metabolism, was central to this network, this gene network may play an important role in regulation of feeding and metabolism in birds.</p

Prior Helicobacter pylori infection ameliorates Salmonella typhimurium-induced colitis: Mucosal crosstalk between stomach and distal intestine

Background: Helicobacter pylori infection is associated with a lower risk of chronic autoimmune diseases including inflammatory bowel disease (IBD). H. pylori modulates the gastric immune response, decreasing the local inflammatory response to itself. In mice, chronic Salmonella typhimurium infection induces colitis similar to Crohn's disease, characterized by inflammation, which progresses toward fibrosis. The aim of this study was to determine whether prior H. pylori infection acts at a distance to modulate the immune response of S. typhimurium -induced colitis. Methods: Mice were infected with the mouse-adapted strain of H. pylori (SS1), followed by infection with S. typhimurium . The effect of H. pylori on colitis was determined by gross pathology, histopathology, cytokine response, and development of fibrosis in the cecum. Gastritis and systemic immune response was measured in response to infection. Results: H. pylori suppresses the Th17 response to S. typhimurium infection in the mouse cecum, but does not alter the Th2 or T-regulatory response or the development of fibrosis. H. pylori infection induces IL-10 in the mesenteric lymph nodes, suggesting an extragastric mechanism for immunomodulation. H. pylori / S. typhimurium coinfection decreases inflammation in both the cecum and the stomach. Conclusions: This study demonstrates a potential mechanism for the negative association between H. pylori and IBD in humans. H. pylori represses the lower gastrointestinal tract Th17 response to bacterially induced colitis via extragastric immunomodulatory effects, illustrating immunological crosstalk between the upper and lower gastrointestinal tract. (Inflamm Bowel Dis 2011;)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/84386/1/21489_ftp.pd

Comparison of noncontrast MRI magnetization transfer and T2‐Weighted signal intensity ratios for detection of bowel wall fibrosis in a Crohn's disease animal model

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113105/1/jmri24815.pd

Ultrasound Shear Wave Elastography Helps Discriminate Low‐grade From High‐grade Bowel Wall Fibrosis in Ex Vivo Human Intestinal Specimens

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135467/1/jum201433122115.pd

Innate Immune Responses of Drosophila Melanogaster are Altered by Spaceflight

Alterations and impairment of immune responses in humans present a health risk for space exploration missions. The molecular mechanisms under pinning innate immune defense can be confounded by the complexity of the acquired immune system of humans. Drosophila (fruit fly) innate immunity is simpler, and shares many similarities with human innate immunity at the level of molecular and genetic pathways. The goals of this study were to elucidate fundamental immune processes in Drosophila affected by spaceflight and to measure host-pathogen responses post-flight. Five containers, each containing ten female and five male fruit flies, were housed and bred on the space shuttle (average orbit altitude of330.35 km) for 12 days and 18.5 hours. A new generation of flies was reared in microgravity. In larvae, the immune system was examined by analyzing plasmatocyte number and activity in culture. In adults, the induced immune responses were analyzed by bacterial clearance and quantitative real-time polymerase chain reaction (qPCR) of selected genes following infection with E. coli. The RNA levels of relevant immune pathway genes were determined in both larvae and adults by microarray analysis. The ability of larval plasmatocytes to phagocytose E. coli in culture was attenuated following spaceflight, and in parallel, the expression of genes involved in cell maturation was down regulated. In addition, the level of constitutive expression of pattern recognition receptors and opsonins that specifically recognize bacteria, and of lysozymes, antimicrobial peptide (AMP) pathway and immune stress genes, hallmarks of humoral immunity, were also reduced in larvae. In adults, the efficiency of bacterial clearance measured in vivo following a systemic infection with E. coli post-flight, remained robust. We show that spaceflight altered both cellular and humoral immune responses in Drosophila and that the disruption occurs at multiple interacting pathways

How does reviewing the evidence change veterinary surgeons' beliefs regarding the treatment of ovine footrot? A quantitative and qualitative study

Footrot is a widespread, infectious cause of lameness in sheep, with major economic and welfare costs. The aims of this research were: (i) to quantify how veterinary surgeons’ beliefs regarding the efficacy of two treatments for footrot changed following a review of the evidence (ii) to obtain a consensus opinion following group discussions (iii) to capture complementary qualitative data to place their beliefs within a broader clinical context. Grounded in a Bayesian statistical framework, probabilistic elicitation (roulette method) was used to quantify the beliefs of eleven veterinary surgeons during two one-day workshops. There was considerable heterogeneity in veterinary surgeons’ beliefs before they listened to a review of the evidence. After hearing the evidence, seven participants quantifiably changed their beliefs. In particular, two participants who initially believed that foot trimming with topical oxytetracycline was the better treatment, changed to entirely favour systemic and topical oxytetracycline instead. The results suggest that a substantial amount of the variation in beliefs related to differences in veterinary surgeons’ knowledge of the evidence. Although considerable differences in opinion still remained after the evidence review, with several participants having non-overlapping 95% credible intervals, both groups did achieve a consensus opinion. Two key findings from the qualitative data were: (i) veterinary surgeons believed that farmers are unlikely to actively seek advice on lameness, suggesting a proactive veterinary approach is required (ii) more attention could be given to improving the way in which veterinary advice is delivered to farmers. In summary this study has: (i) demonstrated a practical method for probabilistically quantifying how veterinary surgeons’ beliefs change (ii) revealed that the evidence that currently exists is capable of changing veterinary opinion (iii) suggested that improved transfer of research knowledge into veterinary practice is needed (iv) identified some potential obstacles to the implementation of veterinary advice by farmers