Hepatocellular oxidant stress following intestinal ischemia-reperfusion injury,

Reperfusion of ischemic intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute hepatic injury is unknown. This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal ischemia-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and oxidized and reduced glutathione. There was no change in hepatic tissue total glutathione following intestinal ischemia--reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29014/1/0000043.pd

Efficacy of anterior gastric fundoplication in the treatment of gastroesophageal reflux in infants and children

Anterior gastric fundoplication (AGF) has been performed at the University of Michigan since 1988. To objectively evaluate the long-term efficacy of the AGF, the authors performed a study of children who had undergone AGF between June 1988 and June 1990 (n = 46). Six of them died of unrelated causes. Twenty-two consented to follow-up evaluation that included parental interview, physical examination, upper gastrointestinal series (UGI), 24-hour esophageal pH probe monitoring (EpH), and a liquid-phase gastric emptying study. Twenty patients (74%) remained asymptomatic, patients exhibited gastroesophageal reflux (GER) by UGI, and three others by EpH. Three children were noted to have delayed gastric emptying. These results compare favorably with data previously reported from this institution of a 5-year follow-up of children after Nissen fundoplication. There is a trend toward improved efficacy (87% v 74%; P = .12), decreased reoperation rate (4% v 14%; P = .11), and less severe complications. The present study shows that AGF is effective treatment for GER when evaluated by objective studies and is comparable in therapeutic efficacy and safety to the Nissen fundoplication.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31949/1/0000902.pd

Molecular Insights into the Pathogenesis of Alzheimer's Disease and Its Relationship to Normal Aging

Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression

Choledochocele: an unusual form of choledochal cyst

Choledochocele, or type III choledochal cyst, is a rare anomaly. Two children with choledochocele, both younger than any previously reported patient, were recently cared for at the University of Michigan Medical Center and prompted a literature review of this subject. Since 1974, 40 cases of choledochocele have been reported with enough clinical information for critical review. Ten of these patients were 21 years of age or younger. Presenting symptoms were not specific for choledochocele; they were generally interpreted to result from other biliary or gastrointestinal disorders that are more common for each age group. In pediatric patients the most frequent signs and symptoms of choledochocele were abdominal pain (70%), nausea and/or vomiting (60%), jaundice (30%), and acute pancreatitis (30%). While two-thirds of adult patients with choledochocele had undergone prior cholecystectomy (with stones rarely found), this was observed only once in children. Obstructive symptoms led to evaluation of the stomach and duodenum with either barium upper GI series or endoscopy in all children. These demonstrated an extrinsic mass effect in 90% of the patients. Endoscopic retrograde cholangiopancreatography identified a choledochocele in all cases in which the study was successfully executed. Intravenous cholangiography was sensitive in children, but less so in the adult patients reviewed. Other imaging efforts (computerized tomography, ultrasound, radionuclide scanning) were less dependable. Transduodenal marsupialization is the treatment of choice for patients of all ages and was provided in both of these newly reported children.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47183/1/383_2004_Article_BF00179633.pd

Effects of ocean sprawl on ecological connectivity: impacts and solutions

The growing number of artificial structures in estuarine, coastal and marine environments is causing “ocean sprawl”. Artificial structures do not only modify marine and coastal ecosystems at the sites of their placement, but may also produce larger-scale impacts through their alteration of ecological connectivity - the movement of organisms, materials and energy between habitat units within seascapes. Despite the growing awareness of the capacity of ocean sprawl to influence ecological connectivity, we lack a comprehensive understanding of how artificial structures modify ecological connectivity in near- and off-shore environments, and when and where their effects on connectivity are greatest. We review the mechanisms by which ocean sprawl may modify ecological connectivity, including trophic connectivity associated with the flow of nutrients and resources. We also review demonstrated, inferred and likely ecological impacts of such changes to connectivity, at scales from genes to ecosystems, and potential strategies of management for mitigating these effects. Ocean sprawl may alter connectivity by: (1) creating barriers to the movement of some organisms and resources - by adding physical barriers or by modifying and fragmenting habitats; (2) introducing new structural material that acts as a conduit for the movement of other organisms or resources across the landscape; and (3) altering trophic connectivity. Changes to connectivity may, in turn, influence the genetic structure and size of populations, the distribution of species, and community structure and ecological functioning. Two main approaches to the assessment of ecological connectivity have been taken: (1) measurement of structural connectivity - the configuration of the landscape and habitat patches and their dynamics; and (2) measurement of functional connectivity - the response of organisms or particles to the landscape. Our review reveals the paucity of studies directly addressing the effects of artificial structures on ecological connectivity in the marine environment, particularly at large spatial and temporal scales. With the ongoing development of estuarine and marine environments, there is a pressing need for additional studies that quantify the effects of ocean sprawl on ecological connectivity. Understanding the mechanisms by which structures modify connectivity is essential if marine spatial planning and eco-engineering are to be effectively utilised to minimise impacts

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference