Uncontrolled combustion of shredded tires in a landfill - Part 1: Characterization of gaseous and particulate emissions.

In summer 2012, a landfill liner comprising an estimated 1.3 million shredded tires burned in Iowa City, Iowa. During the fire, continuous monitoring and laboratory measurements were used to characterize the gaseous and particulate emissions and to provide new insights into the qualitative nature of the smoke and the quantity of pollutants emitted.

Uncontrolled combustion of shredded tires in a landfill -Part 2: Population exposure, public health response, and an air quality index for urban fires.

The Iowa City Landfill in eastern Iowa, United States, experienced a fire lasting 18 days in 2012, in which a drainage layer of over 1 million shredded tires burned, generating smoke that impacted the surrounding metropolitan area of 130,000 people. This emergency required air monitoring, risk assessment, dispersion modeling, and public notification. This paper quantifies the impact of the fire on local air quality and proposes a monitoring approach and an Air Quality Index (AQI) for use in future tire fires and other urban fires.

Human neural stem cells induce functional myelination in mice with severe dysmyelination.

Shiverer-immunodeficient (Shi-id) mice demonstrate defective myelination in the central nervous system (CNS) and significant ataxia by 2 to 3 weeks of life. Expanded, banked human neural stem cells (HuCNS-SCs) were transplanted into three sites in the brains of neonatal or juvenile Shi-id mice, which were asymptomatic or showed advanced hypomyelination, respectively. In both groups of mice, HuCNS-SCs engrafted and underwent preferential differentiation into oligodendrocytes.

A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis.

In a phase 2 clinical trial of annual alemtuzumab for treatment of relapsing-remitting multiple sclerosis, 6 of 216 patients (2.8%) developed immune thrombocytopenia (ITP). Over mean follow-up of 4.

Timing of appearance of late oligodendrocyte progenitors coincides with enhanced susceptibility of preterm rabbit cerebral white matter to hypoxia-ischemia.

Emerging evidence supports that premature infants are susceptible to both cerebral white and gray matter injury. In a fetal rabbit model of placental insufficiency, preterm rabbits at embryonic day 22 (E22) exhibited histologic evidence of gray matter injury but minimal white matter injury after global hypoxia-ischemia (H-I). We hypothesized that the dissociation between susceptibility to gray and white matter injury at E22 was related to the timing of appearance of late oligodendrocyte progenitors (preOLs) that are particularly vulnerable in preterm human white matter lesions.

Venous thromboembolism in the neonatal period.

Thromboembolism occurs more frequently in newborns than in older infants or children. The developing hemostasis system of neonates has decreased concentrations of procoagulant proteins and the naturally occurring anticoagulants and hemostatic control proteins. Overall, neonatal hemostasis provides protection from excessive bleeding at the expense of an increased risk for thromboembolism.

N-methyl-N'-nitro-N-nitrosoguanidine activates multiple cell death mechanisms in human fibroblasts.

Response to genotoxic stress may trigger the activation of distinct mechanisms that serve to promote cell death, including apoptosis and necrosis. In this study we examined the response of human fibroblasts, either proficient or deficient for the damage-activated protein kinase ataxia telangiectasia-mutated (ATM), to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Analysis of both long- and short-term viability shows that both ATM-proficient YZ-5 and ATM-deficient EBS-7 fibroblasts display a cytotoxic response to MNNG.

ITP in the 21st century.

Immune (or idiopathic) thrombocytopenic purpura (ITP) is commonly encountered by the practicing hematologist. Clinical management decisions have traditionally been guided by individual training and past experience. Input from the literature has been more from observational reports of case series than from scientific results of hypothesis-driven research.

Life-threatening sepsis caused by Burkholderia cepacia from contaminated intravenous flush solutions prepared by a compounding pharmacy in another state.

We report 2 life-threatening cases of Burkholderia cepacia sepsis caused by infusate contamination during compounding. Bacterial isolates from the patients' blood cultures and the infusate were indistinguishable by pulsed-field gel electrophoresis. Proper quality controls at a local and national level are important for ensuring safe delivery of compounded medications to patients in all settings, including those outside health care facilities.

Spatial heterogeneity in oligodendrocyte lineage maturation and not cerebral blood flow predicts fetal ovine periventricular white matter injury.

Although periventricular white matter injury (PWMI) is the leading cause of chronic neurological disability and cerebral palsy in survivors of premature birth, the cellular-molecular mechanisms by which ischemia-reperfusion contributes to the pathogenesis of PWMI are not well defined. To define pathophysiologic relationships among ischemia, acute cerebral white matter damage, and vulnerable target populations, we used a global cerebral ischemia-reperfusion model in the instrumented 0.65 gestation fetal sheep.

Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation.

Iron is critical for cell growth and proliferation. Iron chelators are being explored for a number of clinical applications, including the treatment of neurodegenerative disorders, heart disease, and cancer. To uncover mechanisms of action of tachpyridine, a chelator currently undergoing preclinical evaluation as an anticancer agent, cell-cycle analysis was performed.

N-methyl-N'-nitro-N-nitrosoguanidine activates cell-cycle arrest through distinct mechanisms activated in a dose-dependent manner.

S(N)1-alkylating agents, such as the mutagenic and cytotoxic drug N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), robustly activate the DNA damage-responsive G(2) checkpoint. Establishment of this checkpoint is dependent on a functional mismatch repair (MMR) system; however, exposure to high doses of MNNG overrides the requirement for MMR to trigger G(2) arrest. In addition, unlike moderate-dose exposure, in which the G(2) checkpoint is attenuated in ataxia-telangiectasia, mutated (ATM)-deficient cells, high-dose MNNG treatment activates G(2) arrest through an ATM-independent mechanism.

Mosaicism of NK cells in a patient with Wiskott-Aldrich syndrome.

Rare cases of somatic mosaicism resulting from reversion of inherited mutations can lead to the attenuation of blood-cell disorders, including Wiskott-Aldrich syndrome (WAS). The impact of the revertant hematopoietic stem or progenitor cells, particularly their representation in blood-cell populations, is of interest because it predicts the outcome of gene therapy. Here we report an 8-year-old patient with WAS caused by a single nucleotide insertion in the WASP gene that abrogates protein expression.

Developmental changes in diffusion anisotropy coincide with immature oligodendrocyte progression and maturation of compound action potential.

Disruption of oligodendrocyte lineage progression is implicated in the white-matter injury that occurs in cerebral palsy. We have previously published a model in rabbits consistent with cerebral palsy. Little is known of normal white-matter development in perinatal rabbits.

Methylator-induced, mismatch repair-dependent G2 arrest is activated through Chk1 and Chk2.

SN1 DNA methylating agents such as the nitrosourea N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) elicit a G2/M checkpoint response via a mismatch repair (MMR) system-dependent mechanism; however, the exact nature of the mechanism governing MNNG-induced G2/M arrest and how MMR mechanistically participates in this process are unknown. Here, we show that MNNG exposure results in activation of the cell cycle checkpoint kinases ATM, Chk1, and Chk2, each of which has been implicated in the triggering of the G2/M checkpoint response. We document that MNNG induces a robust, dose-dependent G2 arrest in MMR and ATM-proficient cells, whereas this response is abrogated in MMR-deficient cells and attenuated in ATM-deficient cells treated with moderate doses of MNNG.

The monofunctional alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine triggers apoptosis through p53-dependent and -independent pathways.

One of the cellular responses to DNA damaging events is the activation of programmed cell death, also known as apoptosis. Apoptosis is an important process in limiting tumorigenesis by eliminating cells with damaged DNA. This view is reinforced by the finding that many genes with pro-apoptotic function are absent or altered in cancer cells.

Preterm fetal hypoxia-ischemia causes hypertonia and motor deficits in the neonatal rabbit: a model for human cerebral palsy?

Prenatal hypoxia-ischemia to the developing brain has been strongly implicated in the subsequent development of the hypertonic motor deficits of cerebral palsy (CP) in premature and full-term infants who present with neonatal encephalopathy. Despite the enormous impact of CP, there is no animal model that reproduces the hypertonia and motor disturbances of this disorder. We report a rabbit model of in utero placental insufficiency, in which hypertonia is accompanied by marked abnormalities in motor control.

Characterization of the novel amplified in breast cancer-1 (NABC1) gene product.

Positional cloning of the cancer-associated 20q13.2 amplicon identified two genes that display high mRNA levels in breast tumors and here we report the initial characterization of one of these gene products, designated Novel Amplified in Breast Cancer-1 (NABC1). Analysis of the primary structure of the NABC1 protein uncovered two regions of this protein with a high likelihood of forming coiled-coils and assembly of a mouse NABC1 cDNA showed that this protein is conserved between mouse and man.

The disulfide-rich region of platelet glycoprotein (GP) IIIa contains hydrophilic peptide sequences that bind anti-GPIIIa autoantibodies from patients with immune thrombocytopenic purpura (ITP).

Immune thrombocytopenic purpura (ITP) is an autoimmune blood disease caused by autoantibody-mediated destruction of blood platelets. Platelet glycoprotein (GP) IIb/IIIa is a common target for antiplatelet autoantibodies. The present studies were undertaken (1).

Quantitative analysis of perinatal rodent oligodendrocyte lineage progression and its correlation with human.

The development of a rodent model in the perinatal rat or mouse that reproduces the principal features of human perinatal white matter injury (periventricular leukomalacia) has been hampered by uncertainty about the developmental window in the rodent that coincides temporally with cerebral white matter development in the premature infant. We recently determined oligodendrocyte (OL) lineage progression in human cerebral white matter and found that the late OL progenitor (preOL) predominates throughout the high-risk period for periventricular leukomalacia [J. Neurosci.

The mismatch repair system is required for S-phase checkpoint activation.

Defective S-phase checkpoint activation results in an inability to downregulate DNA replication following genotoxic insult such as exposure to ionizing radiation. This 'radioresistant DNA synthesis' (RDS) is a phenotypic hallmark of ataxia-telangiectasia, a cancer-prone disorder caused by mutations in ATM. The mismatch repair system principally corrects nucleotide mismatches that arise during replication.

Pathophysiology of immune thrombocytopenic purpura.

In 1951, the young hematologist in training, Dr. William Harrington, infused himself with plasma from a patient with immune thrombocytopenic purpura (ITP). He rapidly developed severe, but transient, thrombocytopenia and was at risk for serious hemorrhage.

Platelet autoantibodies in immune thrombocytopenic purpura.

In summary, the search for a useful clinical laboratory diagnostic assay for the antiplatelet antibodies has been long and difficult. Measurement of platelet associated IgG (PAIgG) has been disappointing as a way to detect autoantibodies. This is primarily due to the fact that platelets normally contain IgG in their alpha granules in an amount that varies with plasma IgG levels and age of the platelets.