University of Louisville

About: University of Louisville is a education organization based out in Louisville, Kentucky, United States. It is known for research contribution in the topics: Population & Poison control. The organization has 24600 authors who have published 49248 publications receiving 1573346 citations. The organization is also known as: UofL.

Mechanisms of Molecular Mimicry Involving the Microbiota in Neurodegeneration

Abstract: The concept of molecular mimicry was established to explain commonalities of structure which developed in response to evolutionary pressures. Most examples of molecular mimicry in medicine have involved homologies of primary protein structure which cause disease. Molecular mimicry can be expanded beyond amino acid sequence to include microRNA and proteomic effects which are either pathogenic or salutogenic (beneficial) in regard to Parkinson's disease, Alzheimer's disease, and related disorders. Viruses of animal or plant origin may mimic nucleotide sequences of microRNAs and influence protein expression. Both Parkinson's and Alzheimer's diseases involve the formation of transmissible self-propagating prion-like proteins. However, the initiating factors responsible for creation of these misfolded nucleating factors are unknown. Amyloid patterns of protein folding are highly conserved through evolution and are widely distributed in the world. Similarities of tertiary protein structure may be involved in the creation of these prion-like agents through molecular mimicry. Cross-seeding of amyloid misfolding, altered proteostasis, and oxidative stress may be induced by amyloid proteins residing in bacteria in our microbiota in the gut and in the diet. Pathways of molecular mimicry induced processes induced by bacterial amyloid in neurodegeneration may involve TLR 2/1, CD14, and NFκB, among others. Furthermore, priming of the innate immune system by the microbiota may enhance the inflammatory response to cerebral amyloids (such as amyloid-β and α-synuclein). This paper describes the specific molecular pathways of these cross-seeding and neuroinflammatory processes. Evolutionary conservation of proteins provides the opportunity for conserved sequences and structures to influence neurological disease through molecular mimicry.

A randomized multicenter trial to compare long-term functional outcome, quality of life, and complications of surgical procedures for low rectal cancers.

Abstract: The emphasis of surgery for low rectal cancers has undergone a distinct change from the oncologic importance of complete excision, adding a focus on a good functional result and the importance of maintaining quality of life (QOL). Since the late 1960s,1,2 when the colonal anastomosis were first described, surgeons have strived to balance a good oncological outcome with QOL. These efforts are exemplified by use of the circular stapler,3 definition of minimal safe margins,4–6 total mesorectal excision,7 and neoadjuvant therapy. Lazorthes et al8 and Parc et al9 described the colonic J-pouch (JP) as an addition to the technique of coloanal anastomosis aimed at providing the reservoir function that is lacking in a straight coloanal anastomosis (SA). The pouch works by providing a segment of bowel with no functional peristalsis. Although functional outcome improved after a JP there existed evacuation difficulty10,11 that was resolved to some extent by defining the optimal length of a JP12 and level of anastomosis where a reservoir function has an advantage.13 Studies of patients with a colonic JP compared with an SA have shown that the antiperistaltic or reservoir capability of the colonic JP gave a better functional outcome in the short term.10,14,15 However urgency of defecation with the JP has not shown to be decreased by any study.3,12,14,16 Not all patients can have a JP incorporated into a coloanal anastomosis. Limitations to the construction of a JP include a narrow pelvis, a bulky mesentery or large appendices epiploicae, mucosectomy, insufficient colonic length, or extensive diverticular disease.17 In such patients, coloplasty has been suggested as an alternative. Z'Graggen18 and his group first described the coloplasty pouch in a porcine model. This followed its introduction in clinical practice.19,20 The coloplasty pouch is a way of providing a reservoir without the bulk or the loss of length of a JP. Thus, it could potentially fit in a narrow pelvis or when the mesocolon was fat laden and bulky. The exit conduit from the coloplasty reservoir could fit/traverse the anal sphincters as far as an SA can. When the coloplasty pouch was compared with the JP in some randomized, controlled trials (RCT), and limited RCT, it showed results comparable to the JP21,22 and superior to the SA.23 However, no randomized trial has prospectively compared the functional outcome of all 3 procedures. Other procedures described in the quest for achieving a good functional outcome have been the side to end coloanal anastomosis,24,25 which has been shown to have a similar outcome to the JP. The purpose of this prospective RCT was to compare the functional outcome and QOL of patients who undergo a coloanal anastomosis with or without a reservoir for low rectal cancer and to study the complications that occur.

Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Abstract: Conscious pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, for three consecutive days (days 1, 2, and 3). On day 1, pigs received an i.v. infusion of a combination of antioxidants (superoxide dismutase, catalase, and N-2 mercaptopropionyl glycine; group II, n = 9), nisoldipine (group III, n = 6), or vehicle (group I [controls], n = 9). In the control group, systolic wall thickening (WTh) in the ischemic-reperfused region on day 1 remained significantly depressed for 4 h after the 10th reperfusion, indicating myocardial "stunning." On days 2 and 3, however, the recovery of WTh improved markedly, so that the total deficit of WTh decreased by 53% on day 2 and 56% on day 3 compared with day 1 (P < 0.01), indicating the development of a powerful cardioprotective response (late preconditioning against stunning). In the anti-oxidant-treated group, the total deficit of WTh on day 1 was 54% less than in the control group (P < 0.01). On day 2, the total deficit of WTh was 85% greater than that observed on day 1 and similar to that observed on day 1 in the control group. On day 3, the total deficit of WTh was 58% less than that noted on day 2 (P < 0.01). In the nisoldipine-treated group, the total deficit of WTh on day 1 was 53% less than that noted in controls (P < 0.01). On days 2 and 3, the total deficit of WTh was similar to the corresponding values in the control group. These results demonstrate that: (a) in the conscious pig, antioxidant therapy completely blocks the development of late preconditioning against stunning, indicating that the production of reactive oxygen species (ROS) on day 1 is the mechanism whereby ischemia induces the protective response observed on day 2; (b) antioxidant therapy markedly attenuates myocardial stunning on day 1, indicating that ROS play an important pathogenetic role in postischemic dysfunction in the porcine heart despite the lack of xanthine oxidase; (c) although the administration of a calcium-channel antagonist (nisoldipine) is as effective as antioxidant therapy in attenuating myocardial stunning on day 1, it has no effect on late preconditioning on day 2, indicating that the ability of antioxidants to block late preconditioning is not a nonspecific result of the mitigation of postischemic dysfunction on day 1. Generation of ROS during reperfusion is generally viewed as a deleterious process. Our finding that ROS contribute to the genesis of myocardial stunning but, at the same time, trigger the development of late preconditioning against stunning supports a complex pathophysiological paradigm, in which ROS play an immediate injurious role (as mediators of stunning) followed by a useful function (as mediators of subsequent preconditioning).