Showing papers by "Vanderbilt University published in 2001"

Efficacy and safety of recombinant human activated protein C for severe sepsis.

Abstract: Background Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. Methods We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 μg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes i...

Osteoporosis prevention, diagnosis, and therapy

Abstract: OBJECTIVES To clarify the factors associated with prevention, diagnosis, and treatment of osteoporosis, and to present the most recent information available in these areas. PARTICIPANTS From March 27-29, 2000, a nonfederal, nonadvocate, 13-member panel was convened, representing the fields of internal medicine, family and community medicine, endocrinology, epidemiology, orthopedic surgery, gerontology, rheumatology, obstetrics and gynecology, preventive medicine, and cell biology. Thirty-two experts from these fields presented data to the panel and an audience of 699. Primary sponsors were the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institutes of Health Office of Medical Applications of Research. EVIDENCE MEDLINE was searched for January 1995 through December 1999, and a bibliography of 2449 references provided to the panel. Experts prepared abstracts for presentations with relevant literature citations. Scientific evidence was given precedence over anecdotal experience. CONSENSUS PROCESS The panel, answering predefined questions, developed conclusions based on evidence presented in open forum and the literature. The panel composed a draft statement, which was read and circulated to the experts and the audience for public discussion. The panel resolved conflicts and released a revised statement at the end of the conference. The draft statement was posted on the Web on March 30, 2000, and updated with the panel's final revisions within a few weeks. CONCLUSIONS Though prevalent in white postmenopausal women, osteoporosis occurs in all populations and at all ages and has significant physical, psychosocial, and financial consequences. Risks for osteoporosis (reflected by low bone mineral density [BMD]) and for fracture overlap but are not identical. More attention should be paid to skeletal health in persons with conditions associated with secondary osteoporosis. Clinical risk factors have an important but poorly validated role in determining who should have BMD measurement, in assessing fracture risk, and in determining who should be treated. Adequate calcium and vitamin D intake is crucial to develop optimal peak bone mass and to preserve bone mass throughout life. Supplementation with these 2 nutrients may be necessary in persons not achieving recommended dietary intake. Gonadal steroids are important determinants of peak and lifetime bone mass in men, women, and children. Regular exercise, especially resistance and high-impact activities, contributes to development of high peak bone mass and may reduce risk of falls in older persons. Assessment of bone mass, identification of fracture risk, and determination of who should be treated are the optimal goals when evaluating patients for osteoporosis. Fracture prevention is the primary treatment goal for patients with osteoporosis. Several treatments have been shown to reduce the risk of osteoporotic fractures, including those that enhance bone mass and reduce the risk or consequences of falls. Adults with vertebral, rib, hip, or distal forearm fractures should be evaluated for osteoporosis and given appropriate therapy.

The Population Biology of Invasive Species

Abstract: ■ Abstract Contributions from the field of population biology hold promise for understanding and managing invasiveness; invasive species also offer excellent opportunities to study basic processes in population biology. Life history studies and demographic models may be valuable for examining the introduction of invasive species and identifying life history stages where management will be most effective. Evolutionary processes may be key features in determining whether invasive species establish and spread. Studies of genetic diversity and evolutionary changes should be useful for

Evaluation of Delirium in Critically Ill Patients: Validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)

Abstract: ObjectiveTo develop and validate an instrument for use in the intensive care unit to accurately diagnose delirium in critically ill patients who are often nonverbal because of mechanical ventilation.DesignProspective cohort study.SettingThe adult medical and coronary intensive care units of a tertia

Multifactor-Dimensionality Reduction Reveals High-Order Interactions among Estrogen-Metabolism Genes in Sporadic Breast Cancer

Abstract: One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common complex multifactorial human diseases. This challenge is partly due to the limitations of parametric-statistical methods for detection of gene effects that are dependent solely or partially on interactions with other genes and with environmental exposures. We introduce multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, to improve the identification of polymorphism combinations associated with disease risk. The MDR method is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., it assumes no particular inheritance model), and is directly applicable to case-control and discordant-sib-pair studies. Using simulated case-control data, we demonstrate that MDR has reasonable power to identify interactions among two or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control data set, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among four polymorphisms from three different estrogen-metabolism genes. To our knowledge, this is the first report of a four-locus interaction associated with a common complex multifactorial disease.

Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.

Abstract: Blood glucose levels are maintained by the balance between glucose uptake by peripheral tissues and glucose secretion by the liver. Gluconeogenesis is strongly stimulated during fasting and is aberrantly activated in diabetes mellitus. Here we show that the transcriptional coactivator PGC-1 is strongly induced in liver in fasting mice and in three mouse models of insulin action deficiency: streptozotocin-induced diabetes, ob/ob genotype and liver insulin-receptor knockout. PGC-1 is induced synergistically in primary liver cultures by cyclic AMP and glucocorticoids. Adenoviral-mediated expression of PGC-1 in hepatocytes in culture or in vivo strongly activates an entire programme of key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, leading to increased glucose output. Full transcriptional activation of the PEPCK promoter requires coactivation of the glucocorticoid receptor and the liver-enriched transcription factor HNF-4alpha (hepatic nuclear factor-4alpha) by PGC-1. These results implicate PGC-1 as a key modulator of hepatic gluconeogenesis and as a central target of the insulin-cAMP axis in liver.

Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity.

Abstract: Cytochrome P450 (P450) enzymes catalyze a variety of reactions and convert chemicals to potentially reactive products as well as make compounds less toxic. Most of the P450 reactions are oxidations. The majority of these can be rationalized in the context of an FeO3+ intermediate and odd electron abstraction/rebound mechanisms; however, other iron−oxygen complexes are possible and alternate chemistries can be considered. Another issue regarding P450-catalyzed reactions is the delineation of rate-limiting steps in the catalytic cycle and the contribution to reaction selectivity. In addition to the rather classical oxidations, P450s also catalyze less generally discussed reactions including reduction, desaturation, ester cleavage, ring expansion, ring formation, aldehyde scission, dehydration, ipso attack, one-electron oxidation, coupling reactions, rearrangement of fatty acid and prostaglandin hydroperoxides, and phospholipase activity. Most of these reactions are rationalized in the context of high-valent...

Oral Reading Fluency as an Indicator of Reading Competence: A Theoretical, Empirical, and Historical Analysis

Abstract: The purpose of this article is to consider oral reading fluency as an indicator of overall reading competence. We begin by examining theoretical arguments for supposing that oral reading fluency may reflect overall reading competence. We then summarize several studies substantiating this phenomenon. Next, we provide an historical analysis of the extent to which oral reading fluency has been incorporated into measurement approaches during the past century. We conclude with recommendations about the assessment of oral reading fluency for research and practice.

Volunteer work and well-being.

Abstract: Using two waves of panel data from Americans' Changing Lives (House 1995) (N = 2,681), we examine the relationships between volunteer work in the community and six aspects of personal well-being: happiness, life satisfaction, self-esteem, sense of control over life, physical health, and depression. Prior research has more often examined the effects of voluntary memberships than of volunteer work, has used cross-sectional rather than longitudinal data, and, when longitudinal, has emphasized social causation over selection effects. Focusing only on the consequences of volunteer work overlooks the antecedents of human agency. People with greater personality resources and better physical and mental health should be more likely to seek (or to be sought for) community service. Hence, we examine both selection and social causation effects. Results show that volunteer work indeed enhances all six aspects of well-being and, conversely, people who have greater well-being invest more hours in volunteer service. Given this, further understanding of self- versus social-selection processes seems an important next step. Do positive, healthy people actively seek out volunteer opportunities, or do organizations actively recruit individuals of these types (or both)? Explaining how positive consequences flow from volunteer service may offer a useful counterpoint to stress theory, which has focused primarily on negative life experiences and their sequelae.

Smart Dust: communicating with a cubic-millimeter computer

Abstract: Domain-specific integrated development environments can help capture specifications in the form of domain models. These tools support the design process by automating analysis and simulating essential system behavior. In addition, they can automatically generate, configure, and integrate target application components. The high cost of developing domain-specific, integrated modeling, analysis, and application-generation environments prevents their penetration into narrower engineering fields that have limited user bases. Model-integrated computing (MIC), an approach to model-based engineering that helps compose domain-specific design environments rapidly and cost effectively, is particularly relevant for specialized computer-based systems domains-perhaps even single projects. The authors describe how MIC provides a way to compose such environments cost effectively and rapidly by using a metalevel architecture to specify the domain-specific modeling language and integrity constraints. They also discuss the toolset that implements MIC and describe a practical application in which using the technology in a tool environment for the process industry led to significant reductions in development and maintenance costs.

Does the Market Value Environmental Performance

Abstract: Previous studies that attempt to relate environmental to financial performance have often led to conflicting results due to small samples and subjective environmental performance criteria. We report on a study that relates the market value of firms in the S&P 500 to objective measures of their environmental performance. After controlling for variables traditionally thought to explain firm-level financial performance, we find that bad environmental performance is negatively correlated with the intangible asset value of firms. The average ‘intangible liability’ for firms in our sample is $380 million—approximately 9% of the replacement value of tangible assets. We conclude that legally emitted toxic chemicals have a significant effect on the intangible asset value of publicly traded companies. A 10% reduction in emissions of toxic chemicals results in a $34 million increase in market value. The magnitude of these effects varies across industries, with larger losses accruing to the traditionally polluting in...

Campylobacter jejuni Infections: Update on Emerging Issues and Trends

Abstract: Infection with Campylobacter jejuni is one of the most common causes of gastroenteritis worldwide; it occurs more frequently than do infections caused by Salmonella species, Shigella species, or Escherichia coli O157:H7. In developed countries, the incidence of Campylobacter jejuni infections peaks during infancy and again during early adulthood. Most infections are acquired by the consumption and handling of poultry. A typical case is characterized by diarrhea, fever, and abdominal cramps. Obtaining cultures of the organism from stool samples remains the best way to diagnose this infection. An alarming recent trend is the rapid emergence of antimicrobial agent--resistant Campylobacter strains all over the world. Use of antibiotics in animals used for food has accelerated this trend. It is fortunate that complications of C. jejuni infections are rare, and most patients do not require antibiotics. Guillain-Barre syndrome is now recognized as a post-infectious complication of C. jejuni infection, but its incidence is <1 per 1000 infections. Careful food preparation and cooking practices may prevent some Campylobacter infections.

Imaging mass spectrometry: a new technology for the analysis of protein expression in mammalian tissues.

Abstract: 1and has been initially targeted for the analysis of peptides and proteins present on or near the surface of tissue sections 2 . Imaging MS brings a new tool to bear on the problem of unraveling and understanding the molecular complexities of cells. It joins techniques such as immunochemistry and fluorescence microscopy for the study of the spatial arrangement of molecules within biological tissues. Many previous experiments using MS to image samples have focused on the measurement of the distribution of elements and small molecules in biological specimens, including tissue slices and individual cells 3‐5 . An extensive review on imaging by MS can be found in the article by Pacholski and Winograd 6

Identification of functionally variant MDR1 alleles among European Americans and African Americans

Abstract: MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1 ) or a site-directed Ser893 mutation (MDR1*2 ) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.

Across the Great Divide: Knowledge Creation and Transfer Between Practitioners and Academics

Abstract: Observers have long noted a considerable gap between organizational research findings and management practices. Although volumes have been written about the probable causes and consequences of this gap, surprisingly little empirical evidence exists concerning the various viewpoints. The articles in this forum provide data on the role of academic-practitioner relationships in both generating and disseminating knowledge across boundaries. The contributions of each article are summarized in light of recent theories of knowledge creation, and suggestions are made for increasing the value and relevance of future research to both academics and practitioners.

Prostanoid receptors: subtypes and signaling.

Abstract: Cyclooxygenases metabolize arachidonate to five primary prostanoids: PGE2, PGF2α, PGI2, TxA2, and PGD2. These autacrine lipid mediators interact with specific members of a family of distinct G-protein-coupled prostanoid receptors, designated EP, FP, IP, TP, and DP, respectively. Each of these receptors has been cloned, expressed, and characterized. This family of eight prostanoid receptor complementary DNAs encodes seven transmembrane proteins which are typical of G-protein-coupled receptors and these receptors are distinguished by their ligand-binding profiles and the signal transduction pathways activated on ligand binding. Ligand-binding selectivity of these receptors is determined by both the transmembrane sequences and amino acid residues in the putative extracellular-loop regions. The selectivity of interaction between the receptors and G proteins appears to be mediated at least in part by the C-terminal tail region. Each of the EP1, EP3, FP, and TP receptors has alternative splice variants describe...

γ-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase

Abstract: ErbB-4 is a transmembrane receptor tyrosine kinase that regulates cell proliferation and differentiation. After binding of its ligand heregulin (HRG) or activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA), the ErbB-4 ectodomain is cleaved by a metalloprotease. We now report a subsequent cleavage by gamma-secretase that releases the ErbB-4 intracellular domain from the membrane and facilitates its translocation to the nucleus. gamma-Secretase cleavage was prevented by chemical inhibitors or a dominant negative presenilin. Inhibition of gamma-secretase also prevented growth inhibition by HRG. gamma-Secretase cleavage of ErbB-4 may represent another mechanism for receptor tyrosine kinase-mediated signaling.

Suppression of hadrons with large transverse momentum in central Au + Au collisions at √sNN = 130 GeV

Abstract: Transverse momentum spectra for charged hadrons and for neutral pions in the range 1 Gev/c < P-T < 5 GeV/c have been measured by the PHENIX experiment at RHIC in Au + Au collisions at rootS(NN) = 130 GeV. At high p(T) the spectra from peripheral nuclear collisions are consistent with scaling the spectra from p + p collisions by the average number of binary nucleon-nucleon collisions. The spectra from central collisions are significantly suppressed when compared to the binary-scaled p + p expectation, and also when compared to similarly binary-scaled peripheral collisions, indicating a novel nuclear-medium effect in central nuclear collisions at RHIC energies.

Infectious Diseases of the Fetus and Newborn Infant

Abstract: Fifth edition. Edited by Jack S. Remington and Jerome O. Klein. Philadelphia: W.B. Saunders Company, 2001. 1507 pages in one volume, illustrated

Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study

Abstract: Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras incolorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P=0.004, HR 1.3) and overall survival (P=0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P=0.008, HR 1.5, overall survival P=0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P=0.46, HR 1.12, overall survival P=0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. ⌐ 2001 Cancer Research Campaign.

Executive control of visual attention in dual-task situations.

Abstract: A theory of executive control is presented that proposes that executive processes control subordinate processes by manipulating their parameters, reconfiguring them to respond in accord with the current task set. It adopts C. Bundesen's (1990) theory of visual attention (TVA) and R. M. Nosofsky and T. J. Palmeri's (1997) exemplar-based random walk (EBRW) as the theory of subordinate processes. It assumes that a task set is a set of TVA and EBRW parameters sufficient to perform a task and that set switching involves changing those parameters. The theory solves 2 computational problems that emerge in dual-task situations: the binding problem and the serial order problem. It can perform dual tasks in series or in parallel but prefers the serial strategy because it is faster and it solves the binding problem naturally. The theory accounts for concurrence cost, set-switching cost, crosstalk between tasks, and the modulation of crosstalk by task set.

Parental Involvement in Homework

Abstract: The article reviews research on parental involvement in student homework. It is focused on understanding: why parents become involved in their children's homework; which activities and strategies they employ in the course of involvement; how their homework involvement influences student outcomes; and which student outcomes are influenced by parents' involvement. Findings suggest that parents involve themselves in student homework because they believe that they should be involved, believe that their involvement will make a positive difference, and perceive that their children or children's teachers want their involvement. Parents' involvement activities take many forms, from establishing structures for homework performance to teaching for understanding and developing student learning strategies. Operating largely through modeling, reinforcement, and instruction, parents' homework involvement appears to influence student success insofar as it supports student attributes related to achievement (e.g., attitud...

Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1

Abstract: The function of many transmembrane molecules can be altered by cleavage and subsequent release of their ectodomains. We have investigated ectodomain cleavage of the cell-cell adhesion and signal-transducing molecule E-cadherin. The E-cadherin ectodomain is constitutively shed from the surface of MCF-7 and MDCKts.srcC12 cells in culture. Release of the 80 kDa soluble E-cadherin fragment is stimulated by phorbol-12-myristate-13-acetate and is inhibited by overexpression of the tissue inhibitor of metalloproteinases-2. The metalloproteinases matrilysin and stromelysin-1 both cleave E-cadherin at the cell surface and release sE-CAD into the medium. The soluble E-cadherin fragment thus released inhibits E-cadherin functions in a paracrine way, as indicated by induction of invasion into collagen type I and inhibition of E-cadherin-dependent cell aggregation. Our results, therefore, suggest a novel mechanism by which metalloproteinases can influence invasion.

Epidemiology of Invasive Streptococcus pneumoniae Infections in the United States, 1995-1998: Opportunities for Prevention in the Conjugate Vaccine Era

Abstract: ContextPneumococcal polysaccharide vaccine is recommended for elderly persons and adults with certain chronic illnesses. Additionally, a recently licensed pneumococcal 7-valent conjugate vaccine has been recommended for use in young children and could dramatically change the epidemiology of pneumococcal disease.ObjectivesTo assess pneumococcal disease burden in the United States, estimate the potential impact of new vaccines, and identify gaps in vaccine recommendations.Design and SettingAnalysis of data from the Active Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network, an active, population-based system in 9 states.PatientsA total of 15 860 cases of invasive pneumococcal disease occurring between January 1, 1995, and December 31, 1998.Main Outcome MeasuresAge- and race-specific pneumoccocal disease incidence rates per 100 000 persons, case-fatality rates, and vaccine preventability.ResultsIn 1998, overall incidence was 23.2 cases per 100 000, corresponding to an estimated 62 840 cases in the United States. Incidence was highest among children younger than 2 years (166.9) and adults aged 65 years or older (59.7). Incidence among blacks was 2.6 times higher than among whites (95% confidence interval [CI], 2.4-2.8). Overall, 28.6% of case-patients were at least 65 years old and 85.9% of cases in this age group were due to serotypes included in the 23-valent polysaccharide vaccine; 19.3% of case-patients were younger than 2 years and 82.2% of cases in this age group were due to serotypes included in the 7-valent conjugate vaccine. Among patients aged 2 to 64 years, 50.6% had a vaccine indication as defined by the Advisory Committee on Immunization Practices (ACIP). The case-fatality rate among patients aged 18 to 64 years with an ACIP indication was 12.1% compared with 5.4% for those without an indication (relative risk, 2.2; 95% CI, 1.7-2.9).ConclusionsYoung children, elderly persons, and black persons of all ages are disproportionately affected by invasive pneumococcal disease. Current ACIP recommendations do not address a subset of persons aged 18 to 64 years but do include those at highest risk for death from invasive pneumococcal disease.

When Bad Things Turn Good and Good Things Turn Bad: Sequences of Redemption and Contamination in Life Narrative and their Relation to Psychosocial Adaptation in Midlife Adults and in Students

Abstract: Midlife adults (age 35 to 65) and college undergraduates provided lengthy, open-ended narrative accounts of personally meaningful episodes from the past, such as life-story high points, low points, turning points, and earliest memories. The oral (adult) and written (student) narratives were coded for redemption and contamination imagery. In the midlife sample, adults scoring high on self-report measures of generativity showed significantly higher levels of redemption and lower levels of contamination sequences. In both samples, redemption sequences in life narrative accounts were positively associated with self-report measures of psychological well-being, whereas contamination sequences predicted low levels of well-being among midlife adults. In addition, redemption sequence scores were a stronger predictor of well-being than were ratings of the overall affective quality of life-narrative accounts. The results are discussed with respect to the empirical literature of benefit-finding in the face of adversi...

Enzyme-replacement therapy in mucopolysaccharidosis I.

Abstract: Background Mucopolysaccharidosis I is a lysosomal storage disease caused by a deficiency of the enzyme α-L-iduronidase. We evaluated the effect of enzyme-replacement therapy with recombinant human α-L-iduronidase in patients with this disorder. Methods We treated 10 patients with mucopolysaccharidosis I (age, 5 to 22 years) with recombinant human α-L-iduronidase at a dose of 125,000 U per kilogram of body weight given intravenously once weekly for 52 weeks. The patients were evaluated at base line and at 6, 12, 26, and 52 weeks by detailed clinical examinations, magnetic resonance imaging of the abdomen and brain, echocardiography, range-of-motion measurements, polysomnography, clinical laboratory evaluations, measurements of leukocyte α-L-iduronidase activity, and urinary glycosaminoglycan excretion. Results Hepatosplenomegaly decreased significantly in all patients, and the size of the liver was normal for body weight and age in eight patients by 26 weeks. The rate of growth in height and weight had inc...

Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis.

Abstract: The adipocyte fatty-acid-binding protein, aP2, has an important role in regulating systemic insulin resistance and lipid metabolism. Here we demonstrate that aP2 is also expressed in macrophages, has a significant role in their biological responses and contributes to the development of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice also deficient for aP2 showed protection from atherosclerosis in the absence of significant differences in serum lipids or insulin sensitivity. aP2-deficient macrophages showed alterations in inflammatory cytokine production and a reduced ability to accumulate cholesterol esters when exposed to modified lipoproteins. Apoe-/- mice with Ap2+/+ adipocytes and Ap2-/- macrophages generated by bone-marrow transplantation showed a comparable reduction in atherosclerotic lesions to those with total aP2 deficiency, indicating an independent role for macrophage aP2 in atherogenesis. Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis.