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Biomedical subjects

Z Leah Harris

Publications and source records attributed to Z Leah Harris.

11 recordsLinked to original sources
PubMed2006

Abdominal compartment syndrome contributing to failure of extracorporeal membrane oxygenation in an infant with congenital heart disease and sepsis.

OBJECTIVE: To provide the first account of extracorporeal membrane oxygenation therapy failure secondary to abdominal compartment syndrome. DESIGN: Case report. SETTING: Pediatric intensive care unit. PATIENT: A 4-month-old infant with cyanotic congenital heart disease and Escherichia coli sepsis developed abdominal distention and venous return failure on extracorporeal membrane oxygenation. INTERVENTION: Emergency cardiac catheterization and atrial septectomy were performed. MAIN RESULTS: Central venous pressure of 120 mm Hg was measured, confirming the diagnosis of abdominal compartment syndrome. CONCLUSIONS: Abdominal compartment syndrome is a life-threatening condition resulting from an increase in intra-abdominal pressure that compromises abdominal organ perfusion, pulmonary function, and cardiac output. Mortality rates from abdominal compartment syndrome are as high as 60% in adults and children. This report of an infant with congenital heart disease and E. coli sepsis represents the first description of abdominal compartment syndrome that contributed to failure of extracorporeal membrane oxygenation and ultimately death. The pathophysiology, diagnosis, and treatment of abdominal compartment syndrome are also reviewed.

Abdomen↗
PubMed2005

Unexpected role of ceruloplasmin in intestinal iron absorption.

Ferroxidases are essential for normal iron homeostasis in most organisms. The paralogous vertebrate ferroxidases ceruloplasmin (Cp) and hephaestin (Heph) are considered to have nonidentical functions in iron transport: plasma Cp drives iron transport from tissue stores while intestinal Heph facilitates iron absorption from the intestinal lumen. To clarify the function of Cp, we acutely bled Cp-/- mice to stress iron homeostasis pathways. Red cell hemoglobin recovery was defective in stressed Cp-/- mice, consistent with low iron availability. Contrary to expectations, iron was freely released from spleen and liver stores in Cp-/- mice, but intestinal iron absorption was markedly impaired. Phlebotomy of wild-type mice caused a striking shift of Cp from the duodenal epithelium to the underlying lamina propria, suggesting a critical function of Cp in basolateral iron transport. Regulated relocalization of intestinal Cp may represent a fail-safe mechanism in which Cp shares with Heph responsibility for iron absorption under stress.

Animals↗
PubMed2005

Lung isolation in a child with unilateral necrotizing Clostridium perfringens pneumonia.

OBJECTIVE: To describe lung isolation and the selective application of continuous positive airway pressure using an endobronchial blocker in a patient with sickle cell disease and unilateral necrotizing Clostridium perfringens pneumonia. DESIGN: Case report. SETTING: Pediatric intensive care unit. PATIENT: A 12-yr-old male with sickle cell disease developed persistent necrotizing pneumonia of the left lung following exchange transfusion for acute chest syndrome and hyper-hemolytic syndrome. INTERVENTIONS: An endobronchial blocker was placed into the left main stem bronchus for lung isolation and application of continuous positive airway pressure to the left lung for 48 hrs. MEASUREMENTS AND MAIN RESULTS: After 14 days of persistent atelectasis of the left lung despite thorascopic decortication and multiple bronchoscopies, our patient had substantial lung aeration within 48 hrs of continuous positive airway pressure applied via the endobronchial blocker. Lung resection was avoided and the patient was successfully extubated 2 days after removal of the blocker. CONCLUSIONS: This case report demonstrates a therapeutic application of prolonged lung isolation and differential ventilation in a patient with an airway too small for commercially available double-lumen endotracheal tubes. The apparent success of this intervention suggests the feasibility of selective ventilation in pediatric patients and highlights a novel application of the bronchial blocker.

Anti-Bacterial Agents↗
PubMed2004

Immunolocalization and regulation of iron handling proteins ferritin and ferroportin in the retina.

PURPOSE: CNS iron accumulation is associated with several neurodegenerative diseases, including age-related macular degeneration. Intracellular overload of free iron is prevented, in part, by the iron export protein, ferroportin, and the iron storage protein, ferritin. The purpose of this study was to assess retinal localization and regulation of ferroportin and ferritin. METHODS: Normal murine retinas were analyzed by immunohistochemistry to localize ferroportin, cytosolic ferritin, and mitochondrial ferritin, with double-labeling using cell-specific markers to identify cell types. Retinas deficient in the ferroxidases, ceruloplasmin and hephaestin, accumulate iron in their retinas and RPE, while retinas deficient in iron regulatory proteins (IRPs) lack the ability to regulate several proteins involved in iron metabolism; retinas from these knockout mice along with their age matched wild type littermates were also examined to study regulation of ferritin and ferroportin. To enable visualization of label in the retinal pigment epithelial cells, sections from pigmented mice were bleached with H2O2 prior to IHC, a novel use of this technique for study of the RPE. RESULTS: In normal retinas, cytosolic ferritins were found predominantly in rod bipolar cells and photoreceptors. Ferroportin was found in RPE and Müller cells. Iron accumulation in mice deficient in ceruloplasmin and hephaestin was associated with upregulation of ferritin and ferroportin. Mice deficient in IRPs showed upregulation of ferritin and ferroportin, likely because of their inability to repress translation. CONCLUSIONS: Normal retinas contain ferritin and ferroportin, whose levels are regulated by iron-responsive, iron regulatory proteins. Ferroportin colocalizes with ceruloplasmin and hephaestin to RPE and Müller cells, supporting a potential cooperation between these ferroxidases and the iron exporter. Cytosolic ferritin accumulates in rod bipolar synaptic terminals, suggesting that ferritin may be involved in axonal iron transport. Mitochondrial ferritin increases with iron accumulation, suggesting a role in iron storage.

Animals↗
PubMed2004

Influence of gestational age and fetal iron status on IRP activity and iron transporter protein expression in third-trimester human placenta.

Placental iron transport during the last trimester of pregnancy determines the iron endowment of the neonate. Iron transport is a function of the major iron transport proteins: transferrin receptor-1 (TfR-1) and ferroportin-1 (FPN-1). The mRNAs for TfR-1 and, potentially, FPN-1 are posttranscriptionally regulated by iron regulatory protein (IRP)-1 and IRP-2. We assessed the effect of gestational age and fetal iron status on IRP-1- and IRP-2-binding activity and on the localization and protein expression of TfR-1 and FPN-1 protein at 24-40 wk of gestation in 21 placentas obtained from iron-sufficient nonanemic mothers. Gestational age had no effect on cord serum ferritin concentration, IRP-2 RNA-binding activity, transporter protein location, and TfR-1 or FPN-1 protein expression. IRP-1 activity remained constant until full term, when it decreased (P = 0.01). Placental ferritin (r = 0.76, P < 0.001) and FPN-1 (r = 0.44, P < 0.05) expression increased with gestational age. Fetal iron status, as indexed by cord serum ferritin concentration, was inversely related to placental IRP-1 (r = -0.66, P < 0.001) and IRP-2 (r = -0.42, P = 0.05) activities. Placental ferritin protein expression correlated better with IRP-1 (r = -0.45, P = 0.04) than with IRP-2 (r = -0.35, P = 0.10) activity. Placental TfR-1 and FPN-1 protein expression was independent of fetal or placental iron status and IRP activities. Iron status had no effect on transport protein localization. We conclude that, toward the end of the third trimester of iron-sufficient human pregnancy, the placenta accumulates ferritin and potentially increases placental-fetal iron delivery through increased FPN-1 expression. IRP-1 may have a more dominant role than IRP-2 activity in regulating ferritin expression.

Adult↗
PubMed2004

A fungal multicopper oxidase restores iron homeostasis in aceruloplasminemia.

Mutations that lead to a loss of the copper-containing plasma enzyme ceruloplasmin disrupt mammalian iron homeostasis. The mechanism by which ceruloplasmin mobilizes iron from cell stores has been controversial. We demonstrate that injection of a soluble copper-containing yeast protein Fet3p can restore iron homeostasis in phlebotomized mice with a deletion of the ceruloplasmin gene. These results show the conservation of function of copper-containing proteins in eukaryotic iron metabolism.

Animals↗
PubMed2004

Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis.

In 1987, Miyajima et al. first characterized an autosomal recessive, adult-onset neurodegenerative disorder resembling Parkinson's disease associated with near-absent circulating serum ceruloplasmin levels. Coined "familial apoceruloplasmin deficiency", they described a patient with a presenting triad of diabetes mellitus, retinal degeneration, and neurodegeneration with blepharospasm. Neuropathological evaluation revealed abundant iron deposition in selected neurons of the basal ganglia and substantia nigra with associated neuronal dropout and spongioform degeneration without evidence of reactive gliosis. Subsequently, mutations in the ceruloplasmin gene have been determined to result in the excessive iron accumulation seen in the pancreas, retina, and brain. Elevated serum ferritin suggests a systemic iron overload syndrome, yet affected patients had low transferrin saturation and a mild anemia. This new disease, "aceruloplasminemia", reveals a role for ceruloplasmin as an essential ferroxidase critical for iron homeostasis. This multicopper oxidase promotes efficient iron efflux such that individuals lacking ceruloplasmin develop a presumed oxidative injury secondary to iron accumulation and significant neuronal damage. Aceruloplasminemic mice provide a valuable model to further study the mechanisms by which ceruloplasmin regulates iron trafficking and the role of iron in oxidative injury. Despite the dependence of ceruloplasmin on copper for its function, aceruloplasminemia represents an iron storage disease and not a defect in copper metabolism. However, recent evidence in Saccharomyces cerevisiae indicates that Fet3, the yeast homologue of ceruloplasmin, functions as an essential cuprous oxidase. Further investigation into the mechanisms by which ceruloplasmin regulates iron and copper homeostasis will provide valuable insight into the pathogenesis of metallo-mediated diseases and elucidate mechanisms for transition metal (copper, iron) neuropathology.

Animals↗
PubMed2003

Genetic defects in copper metabolism.

Genetic defects in copper metabolism highlight the delicate balance mammalian systems have developed to maintain normal copper homeostasis. Menkes disease, the mottled mouse, the Atox-1-deficient mouse and the ctr1 knockout mouse reveal the importance of adequate copper intake during embryogenesis and early development, especially in the central nervous system. The toxicity associated with excess copper as manifest in Wilson disease, the toxic milk mouse, the LEC rat and copper toxicosis in the Bedlington terrier demonstrate the profound cellular susceptibility to copper overload, in particular, in the brain and liver. Ceruloplasmin (Cp) contains 95% of the copper found in human serum, and inherited loss of this protein results in diabetes, retinal degeneration and neurodegeneration. Despite normal copper metabolism, aceruloplasminemic patients and the Cp knockout mouse have disturbed iron homeostasis and mild hepatic copper retention. These genetic disorders of copper metabolism provide valuable insight into the mechanisms regulating copper homeostasis and models to further dissect the role of this essential metal in health and disease.

Biological Transport↗
PubMed2002

Fe(III)-mediated cellular toxicity.

Because it can undergo reversible changes in oxidation state, iron is an excellent biocatalyst but also a potentially deleterious metal. Iron-mediated toxicity has been ascribed to Fe(II), which reacts with oxygen to generate free radicals that damage macromolecules and cause cell death. However, we now report that Fe(III) exhibits microbicidal activity towards strains of Salmonella enterica, Escherichia coli and Klebsiella pneumoniae defective in the Fe(III)-responding PmrA/PmrB signal transduction system. Fe(III) bound to a pmrA Salmonella mutant more effectively than to the isogenic wild-type strain and exerted its microbicidal activity even under anaerobic conditions. Moreover, Fe(III) permeabilized the outer membrane of the pmrA mutant, rendering it susceptible to vancomycin, which is normally non-toxic to Gram-negative species. On the other hand, Fe(III) did not affect the viability of a mutant defective in Fur, the major regulator of cytosolic iron homeostasis, which is hypersensitive to Fe(II)-mediated toxicity. A functional pmrA gene was necessary for bacterial survival in soil. Our results indicate that Fe(III) exerts its microbicidal activity by a mechanism that is oxygen independent and different from that mediated by Fe(II).

Bacterial Proteins↗