Early and sustained improvement in fatigue-related quality of life following red blood cell transfusion in outpatients.

PURPOSE: Outpatients with hematologic disease often receive red cell transfusion to treat anemia and fatigue. The effect of transfusion on fatigue-related quality of life and how well this effect is sustained has not been quantified. The study aim was to describe the early and sustained impact over 4 weeks of red cells on patient-reported fatigue in outpatients age ≥ 50 receiving transfusion as routine clinical care. METHODS: FACIT-Fatigue scale scores were measured pre-transfusion and at visits targeting 3, 7, and 28 days post-transfusion. Group-based trajectory modeling of patient fatigue scores by study day was used to identify the number of distinct trajectories (Groups), then longitudinal mixed effects modeling of fatigue scores was used to estimate group-specific mean improvements early after transfusion and between days 3 and 28 post-transfusion. RESULTS: Four distinct fatigue score trajectory groups were identified and were found to be correlated with baseline fatigue scores (means 12, 26, 34, and 47 points). In the three groups with the lowest fatigue trajectories (indicating greater fatigue), improvements in fatigue early after transfusion achieved the established minimum clinically important difference (≥ 3 points, Group p = 0.0039). In all trajectory groups, mean fatigue levels did not change significantly between 3 and 28 days (± 1 point, Group p = 0.60). CONCLUSION: Patient-reported fatigue varies widely among older adult outpatients with hematologic disorders. Nonetheless, trajectory modeling suggests that most anemic patients can expect a noticeable improvement in fatigue in the first few days after transfusion that generally is sustained up to 4 weeks.

The impact of recipient factors on the lower-than-expected hemoglobin increment in transfused outpatients with hematologic diseases.

BACKGROUND: Patients with cancer or chronic hematologic disorders frequently receive red blood cell (RBC) transfusions. Based on long-standing assumptions, each RBC unit is thought to increase recipient hemoglobin by 1 g/dL, but smaller increments can occur. A better understanding of recipient factors affecting hemoglobin increments could help providers manage these patients. METHODS: Data were collected as a part of the observational Red Cells in Outpatients Transfusion Outcomes (RETRO) study of outpatients with hematologic or cancer-related diagnoses. Hemoglobin was measured before transfusion and 30 minutes after transfusion. A classification and regression tree (CART) analysis was performed to identify statistically significant associations with clinical variables. A corresponding prediction equation was developed and validated using linear regression. RESULTS: A total of 195 participants had both pre- and posttransfusion hemoglobin values for analysis. The median age was 66 years, and patients received one (73%) or two (27%) RBC units during the transfusion episode. The overall median change in hemoglobin was 0.6 g/dL per RBC unit. Both CART analysis and linear regression identified the following significant predictors of hemoglobin increment: number of units received (positive correlation), patient estimated circulating blood volume (negative correlation), pretransfusion hemoglobin (negative correlation), and patient age (negative correlation). CONCLUSION: In this study of outpatients with hematologic disease, most patients had a hemoglobin increment of less than 1 g/dL/unit. Recipient-specific factors influenced the hemoglobin increment at 30 minutes, and providers should consider circulating blood volume, pretransfusion hemoglobin, and recipient age, when developing patient-specific RBC transfusion plans for this unique cohort.

Therapeutic impact of red blood cell transfusion on anemic outpatients: the RETRO study.

BACKGROUND: Patients with cancer or other diagnoses associated with chronic anemia often receive red blood cell (RBC) transfusion as outpatients, but the effect of transfusion on functional status is not well demonstrated. STUDY DESIGN AND METHODS: To estimate the effect of transfusion on functional status and quality of life, we measured 6-minute walk test distance and fatigue- and dyspnea-related quality-of-life scores before and 1 week after RBC transfusion in 208 outpatients age ≥50 with at least one benign or malignant hematology/oncology diagnosis. To account for potential confounding effects of cancer treatment, patients were classified into two groups based on cancer treatment within 4 weeks of the study transfusion. Minimum clinically important improvements over baseline were 20 meters in walk test distance, 3 points in fatigue score, and 2 points in dyspnea score. RESULTS: The median improvement in unadjusted walk test distance was 20 meters overall and 30 meters in patients not receiving recent cancer treatment. Fatigue scores improved overall by a median of 3 points and by 4 points in patients without cancer treatment. There was no clinically important change in dyspnea scores. In multiple linear regression analysis, patients who maintained hemoglobin (Hb) levels of 8 g/dL or greater at 1 week posttransfusion, who had not received recent cancer treatment, and who did not require hospitalization during the study showed clinically important increases in mean walk test distance. CONCLUSIONS: Red blood cell transfusion is associated with a modest, but clinically important improvement in walk test distance and fatigue score outcomes in adult hematology/oncology outpatients.

Clinical effects of red blood cell storage.

BACKGROUND: Well-characterized biochemical, structural, and physiological changes occur when red blood cells (RBCs) are stored for a period of time and are collectively called the storage lesion. METHODS: Key study results are summarized and contrasted and new data from recently completed randomized controlled trials will be discussed. RESULTS: It is unclear whether in vitro changes to RBCs that occur during storage are clinically relevant. The clinical effects of RBC storage have been the focus of observational studies in recent years. However, these studies lack any consensus, possibly because of methodological limitations. CONCLUSIONS: The clinical significance of storing RBCs is controversial, although new data from randomized controlled trials of neonates and patients undergoing cardiac surgery suggest that the duration of RBC storage is not associated with adverse clinical outcomes in these patient populations.

Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion.

BACKGROUND: Intravascular red cell hemolysis impairs nitric oxide (NO)-redox homeostasis, producing endothelial dysfunction, platelet activation, and vasculopathy. Red blood cell storage under standard conditions results in reduced integrity of the erythrocyte membrane, with formation of exocytic microvesicles or microparticles and hemolysis, which we hypothesized could impair vascular function and contribute to the putative storage lesion of banked blood. METHODS AND RESULTS: We now find that storage of human red blood cells under standard blood banking conditions results in the accumulation of cell-free and microparticle-encapsulated hemoglobin, which, despite 39 days of storage, remains in the reduced ferrous oxyhemoglobin redox state and stoichiometrically reacts with and scavenges the vasodilator NO. Using stopped-flow spectroscopy and laser-triggered NO release from a caged NO compound, we found that both free hemoglobin and microparticles react with NO about 1000 times faster than with intact erythrocytes. In complementary in vivo studies, we show that hemoglobin, even at concentrations below 10 µmol/L (in heme), produces potent vasoconstriction when infused into the rat circulation, whereas controlled infusions of methemoglobin and cyanomethemoglobin, which do not consume NO, have substantially reduced vasoconstrictor effects. Infusion of the plasma from stored human red blood cell units into the rat circulation produces significant vasoconstriction related to the magnitude of storage-related hemolysis. CONCLUSIONS: The results of these studies suggest new mechanisms for endothelial injury and impaired vascular function associated with the most fundamental of storage lesions, hemolysis.

Red blood cell microparticles show altered inflammatory chemokine binding and release ligand upon interaction with platelets.

BACKGROUND: Storage of red blood cells (RBCs) under standard blood bank conditions results in reduced structural integrity leading to membrane budding and release of microparticles. Microparticles express the blood group Duffy antigen known to bind multiple inflammatory chemokines, but the functional chemokine binding properties of microparticles are not known. STUDY DESIGN AND METHODS: We determined whether storage-induced microparticles show inflammatory chemokine binding through the expression of the Duffy antigen, comparing the binding properties to intact RBCs, and assessed microparticle interactions with platelets (PLTs) that release chemokines upon activation. RESULTS: Intact RBCs retained similar equilibrium dissociation constants for CCL2 (Kd = 7.4 ± 0.9 nmol/L), CXCL8 (Kd = 7.9 ± 1.0 nmol/L), and CXCL1 (Kd = 4.4 ± 1.0 nmol/L) throughout storage. In contrast, microparticles increased in relative counts with storage, showed higher percentages of surface phosphatidylserine, and demonstrated impaired Duffy-dependent chemokine binding affinity with wider variability in dissociation constant for CXCL1(Kd = 362 ± 328 nmol/L; range, 0.6-2000 nmol/L). The altered chemokine binding affinity of RBC microparticles was associated with a propensity to release ligand upon incubation with PLTs. Relative quantification of microparticles, based on criteria of glycophorin A expression and size, underestimated particle numbers with functional chemokine binding, suggesting that glycophorin A-negative particles and nanoparticles contribute to overall chemokine binding capacity. CONCLUSION: Microparticle burden in transfusates, as determined by functional chemokine binding, is considerable. Altered membrane properties of RBC microparticles enhance PLT interactions to increase inflammatory chemokine bioavailability in vitro.

Outcomes of previously healthy pediatric patients with fulminant sepsis-induced multisystem organ failure receiving therapeutic plasma exchange.

BACKGROUND: Fulminant sepsis-induced multisystem organ failure (MSOF) in pediatric patients carries substantial morbidity and mortality. Therapeutic plasma exchange (TPE) has been reported to be beneficial in sepsis-induced MSOF. We evaluated the outcomes of previously healthy children with fulminant sepsis-induced MSOF receiving TPE. MATERIALS AND METHODS: Previously healthy pediatric ICU patients who underwent TPE for MSOF due to fulminant bacterial sepsis were retrospectively reviewed. Eleven patients (three females and eight males) with age ranging 8 months to 14 years were identified (eight meningococcemia and three other infections). All patients received daily TPE with fresh frozen plasma (FFP) as replacement fluid. Organ failure index (OFI-maximum score = 6) was assessed daily for 7 days. RESULTS: A median of 4 TPE (1-14) were performed. Improvements in organ function and platelet count occurred in most patients with 2-4 TPE treatments. All 10 patients who were alive had reduced OFI to 2 by day 7 of initial TPE and were all fully recovered (survival rate = 10/11, 91%). The only death occurred in a patient who died the same day after his first TPE treatment, which was initiated 24 h after development of MSOF. The 10 survivors underwent early initiation of TPE (median 5.3 h) after the onset of MSOF. CONCLUSIONS: > TPE may contribute to a better outcome in previously healthy pediatric patients with fulminant sepsis-induced MSOF, especially if instituted early in the course of multiorgan failure.

Human herpesvirus 8 genomes and seroprevalence in United States blood donors.

BACKGROUND: Human herpesvirus 8 (HHV-8) is a gamma-herpesvirus that causes Kaposi's sarcoma. The prevalence of HHV-8 genomes in US blood donors has not been systemically studied. STUDY DESIGN AND METHODS: A sensitive and quantitative real-time polymerase chain reaction (PCR) assay was used to detect HHV-8 DNA from purified CD19+ B lymphocytes from randomly selected US whole blood donors. Cellular target for the GAPDH gene was used to quantify cell-equivalent DNA. HHV-8 PCR was run in duplicate for each donor specimen along with an HHV-8 genomic copy standard. HHV-8 antibodies were detected by an indirect immunofluorescence assay. RESULTS: Specimens were obtained from 962 blood donors. DNA from more than 3 x 10(5) B-cell equivalents were obtained from 684 donors. No HHV-8 DNA was detected from any of the blood donor specimens. For the 684 donors, HHV-8 genomes were not detected in the DNA equivalent of 3 x 10(5) to 6 x 10(5) CD19+ B cells with real-time PCR, which has a detection limit of eight copies (95% confidence interval, 0-3/684). Negative results from the remaining 220 donors were potentially confounded by insufficient input DNA into the PCR procedures. Antibodies to HHV-8 were detected in 7.3% (70/962) of the donors. HHV-8 genomes were not detected from 40 of 70 HHV-8-seropositive donor B-cell DNA samples. CONCLUSION: The results indicate that the prevalence of detectable HHV-8 genomes in healthy blood donors is very low.

Effects of storage and leukoreduction on lymphocytes and Epstein-Barr virus genomes in platelet concentrates.

BACKGROUND: Epstein-Barr virus (EBV) persists in infected B lymphocytes in blood donors. Lymphocytes are viable during platelet (PLT) storage. The effects of storage and leukoreduction on lymphocytes and EBV genomes are evaluated. STUDY DESIGN AND METHODS: Forty nonleukoreduced PLT concentrates were stored at 20 to 24°C for up to 7 days. EBV genomes in B cells were quantified on Days 1 and 5. Viable white blood cells (WBCs) and T and B cells were quantified in 10 of 40 units on Days 1, 3, 5, and 7 of storage. For the leukoreduction study, four pools of PLTs were leukoreduced within 24 hours of collection. B cells from before leukoreduction and all peripheral blood mononuclear cells from after leukoreduction were assayed for EBV. RESULTS: Viable WBCs and T cells were stable whereas viable B cells were reduced to 71% of the Day 1 level by Day 5. A total of 31 of 37 (83.8%) units were EBV positive. Although EBV genomes remained stable in most units, 12 of 37 units demonstrated a median of 5.1 (range 2- to 134)-fold increase in EBV genomes per 105 B cells on Day 5. For the leukoreduction study, EBV genomes were detected in four of four pools before leukoreduction with a median of 3.8 (range, 0.2-93.6) EBV genomes per 105 B cells. EBV genomes were not detected in any of the postleukoreduction specimens. CONCLUSIONS: Seventy percent of B lymphocytes are viable on Day 5 of PLT storage. Although the mean number of EBV genomes remained stable, a subset of units had increased EBV genomes during storage. Leukoreduction removed polymerase chain reaction-detectable EBV genomes from PLT pools.

Benefits of reducing prenatal exposure to coal-burning pollutants to children's neurodevelopment in China.

BACKGROUND: Coal burning provides 70% of the energy for China's industry and power, but releases large quantities of polycyclic aromatic hydrocarbons (PAHs) and other pollutants. PAHs are reproductive and developmental toxicants, mutagens, and carcinogens. OBJECTIVE: We evaluated the benefit to neurobehavioral development from the closure of a coal-fired power plant that was the major local source of ambient PAHs. METHODS: The research was conducted in Tongliang, Chongqing, China, where a coal-fired power plant operated seasonally before it was shut down in May 2004. Two identical prospective cohort studies enrolled nonsmoking women and their newborns in 2002 (before shutdown) and 2005 (after shutdown). Prenatal PAH exposure was measured by PAH-DNA adducts (benzo[a]pyrene-DNA) in umbilical cord blood. Child development was assessed by the Gesell Developmental Schedules at 2 years of age. Prenatal exposure to other neurotoxicants and potential confounders (including lead, mercury, and environmental tobacco smoke) was measured. We compared the cohorts regarding the association between PAH-DNA adduct levels and neurodevelopmental outcomes. RESULTS: Significant associations previously seen in 2002 between elevated adducts and decreased motor area developmental quotient (DQ) (p = 0.043) and average DQ (p = 0.047) were not observed in the 2005 cohort (p = 0.546 and p = 0.146). However, the direction of the relationship did not change. CONCLUSION: The findings indicate that neurobehavioral development in Tongliang children benefited by elimination of PAH exposure from the coal-burning plant, consistent with the significant reduction in PAH-DNA adducts in cord blood of children in the 2005 cohort. The results have implications for children's environmental health in China and elsewhere.

Shorter telomere length in cord blood associated with prenatal air pollution exposure: Benefits of intervention.

BACKGROUND: To examine the molecular benefits of the government action to close the local coal burning power plant in Tongliang County, Chongqing Municipality, we compared biologic markers and health outcomes in two successive birth cohorts enrolled before and after the plant was shut down. In this city, polycyclic aromatic hydrocarbons (PAH) were primarily emitted by the coal burning facility. We previously reported that cord blood levels of PAH-DNA adducts (a biomarker of exposure) and various adverse health outcomes were reduced in the second cohort, whereas levels of brain-derived neurotrophic factor/BDNF (a protein involved in neuronal growth) were increased. Here we assessed telomere length (TL), which has been associated with risk of certain chronic diseases, early mortality, aging and cognitive decline in adults. OBJECTIVES: The goals of the present study were to determine whether TL differed between the two cohorts and whether prenatal PAH exposure, estimated by PAH-DNA adducts in cord white blood cells of newborns in China, were predictive of shorter TL in cord blood, suggesting the potential accrual of risk of certain chronic diseases during the prenatal period. We explored relationships of TL with BDNF and neurodevelopmental outcomes, each previously associated with PAH-DNA adducts in these cohorts, as well as the potential mediating role of TL in the associations between adducts and neurodevelopmental outcomes. METHODS: We analyzed TL in cord blood of 255 newborns who also had data on PAH-DNA adducts, BDNF, and relevant covariates. Multiple regression analysis was carried out to test associations between adducts and TL and between TL and BDNF, adjusting for relevant covariates. In the subset with developmental quotient (DQ) scores from Gesell testing at age 2 (N = 210), we explored whether TL was a mediator of the relationship between PAH-DNA adducts and DQ scores by first examining the associations between cord adducts and DQ, cord adducts and TL, and TL and DQ, adjusting for the same covariates. RESULTS: As hypothesized, the mean TL was significantly higher in the second cohort compared to the first cohort. Overall, PAH-DNA cord adducts were significantly and inversely correlated with TL. Multiple regression analysis showed a significant association between adducts and TL, after adjusting for key covariates: ß (effect size per standard deviation adducts) = -0.019, p = .003. The regression coefficient of TL on (Ln) BDNF was also significant (ß = 0.167, p < .001). Exploratory analysis, regressing TL on Gesell developmental scores, showed generally inverse, but not significant associations. TL was not, therefore, deemed to be a potential mediator of the association between adducts and developmental scores at age two. CONCLUSION: This study provides the first evidence that prenatal PAH exposure from coal burning may adversely affect TL, with potential implications for future risk of chronic diseases including cardiovascular disease. The improvement in TL in the second cohort and the observed correlation between increased TL and higher levels of BDNF indicate direct benefits to the health and development of children resulting from the government's closure of the power plant.

PAH-DNA adducts in cord blood and fetal and child development in a Chinese cohort.

Polycyclic aromatic hydrocarbons (PAHs) are an important class of toxic pollutants released by fossil fuel combustion. Other pollutants include metals and particulate matter. PAH-DNA adducts, or benzo[a]pyrene (BaP) adducts as their proxy, provide a chemical-specific measure of individual biologically effective doses that have been associated with increased risk of cancer and adverse birth outcomes. In the present study we examined the relationship between prenatal PAH exposure and fetal and child growth and development in Tongliang, China, where a seasonally operated coal-fired power plant was the major pollution source. In a cohort of 150 nonsmoking women and their newborns enrolled between 4 March 2002 and 19 June 2002, BaP-DNA adducts were measured in maternal and umbilical cord blood obtained at delivery. The number of gestational months occurring during the period of power plant operation provided a second, more general measure of exposure to plant emissions, in terms of duration. High PAH-DNA adduct levels (above the median of detectable adduct level) were associated with decreased birth head circumference (p=0.057) and reduced children's weight at 18 months, 24 months, and 30 months of age (p<0.05), after controlling for potential confounders. In addition, in separate models, longer duration of prenatal exposure was associated with reduced birth length (p=0.033) and reduced children's height at 18 (p=0.001), 24 (p<0.001), and 30 months of age (p<0.001). The findings suggest that exposure to elevated levels of PAHs, with the Tongliang power plant being a significant source, is associated with reduced fetal and child growth in this population.

Molecular evidence of an interaction between prenatal environmental exposures and birth outcomes in a multiethnic population.

Inner-city, minority populations are high-risk groups for adverse birth outcomes and also are more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene (BaP), and other polycyclic aromatic hydrocarbons (PAHs) found in urban air. In a sample of nonsmoking African-American and Dominican women, we evaluated the effects on birth outcomes of prenatal exposure to ETS, using questionnaire data and plasma cotinine as a biomarker of exposure, and environmental PAHs using BaP-DNA adducts as a molecular dosimeter. We previously reported that among African Americans, high prenatal exposure to PAHs estimated by prenatal personal air monitoring was associated with lower birth weight (p = 0.003) and smaller head circumference (p = 0.01) after adjusting for potential confounders. In the present analysis, self-reported ETS was associated with decreased head circumference (p = 0.04). BaP-DNA adducts were not correlated with ETS or dietary PAHs. There was no main effect of BaP-DNA adducts on birth outcomes. However, there was a significant interaction between the two pollutants such that the combined exposure to high ETS and high adducts had a significant multiplicative effect on birth weight (p = 0.04) and head circumference (p = 0.01) after adjusting for ethnicity, sex of newborns, maternal body mass index, dietary PAHs, and gestational age. This study provides evidence that combined exposure to environmental pollutants at levels currently encountered in New York City adversely affects fetal development.

Molecular and neurodevelopmental benefits to children of closure of a coal burning power plant in China.

Polycyclic aromatic hydrocarbons (PAH) are major toxic air pollutants released during incomplete combustion of coal. PAH emissions are especially problematic in China because of their reliance on coal-powered energy. The prenatal period is a window of susceptibility to neurotoxicants. To determine the health benefits of reducing air pollution related to coal-burning, we compared molecular biomarkers of exposure and preclinical effects in umbilical cord blood to neurodevelopmental outcomes from two successive birth cohorts enrolled before and after a highly polluting, coal-fired power plant in Tongliang County, China had ceased operation. Women and their newborns in the two successive cohorts were enrolled at the time of delivery. We measured PAH-DNA adducts, a biomarker of PAH-exposure and DNA damage, and brain-derived neurotrophic factor (BDNF), a protein involved in neuronal growth, in umbilical cord blood. At age two, children were tested using the Gesell Developmental Schedules (GDS). The two cohorts were compared with respect to levels of both biomarkers in cord blood as well as developmental quotient (DQ) scores across 5 domains. Lower levels of PAH-DNA adducts, higher concentrations of the mature BDNF protein (mBDNF) and higher DQ scores were seen in the 2005 cohort enrolled after closure of the power plant. In the two cohorts combined, PAH-DNA adducts were inversely associated with mBDNF as well as scores for motor (p = 0.05), adaptive (p = 0.022), and average (p = 0.014) DQ. BDNF levels were positively associated with motor (p = 0.018), social (p = 0.001), and average (p = 0.017) DQ scores. The findings indicate that the closure of a coal-burning plant resulted in the reduction of PAH-DNA adducts in newborns and increased mBDNF levels that in turn, were positively associated with neurocognitive development. They provide further evidence of the direct benefits to children's health as a result of the coal plant shut down, supporting clean energy and environmental policies in China and elsewhere.

Predictors and consequences of global DNA methylation in cord blood and at three years.

DNA methylation changes have been implicated in many common chronic diseases leading to the hypothesis that environmental and age-related DNA methylation changes within individuals are involved in disease etiology. Few studies have examined DNA methylation changes within an individual over time and all of these studies have been conducted in adults. Here, we aim to characterize how global DNA methylation changes from birth to age three within a longitudinal birth cohort study and to determine whether there are consistent predictors of DNA methylation levels measured three years apart. We measured global DNA methylation in the same children at birth (cord blood) and again at three years of age among 165 children, using an immunoassay. We found that on average, DNA methylation was significantly higher in blood at age 3-years than in cord blood (p<0.01). However, for any individual child, the difference was less than would be expected by chance. We found that pre-pregnancy BMI was negatively predictive of both cord and three-year DNA methylation, even after statistical adjustment to account for the correlation between cord blood and three-year DNA methylation. The biologic implications of small changes in global DNA methylation are unknown. However, the observation that global DNA methylation levels persist within an individual from birth to age three supports the belief that factors that influence global DNA methylation, including pre-pregnancy BMI, may confer long-term effects.

Effects of prestorage vs poststorage leukoreduction on the rate of febrile nonhemolytic transfusion reactions to platelets.

The purpose of this study was to assess the incidence of febrile nonhemolytic transfusion reactions (FNHTRs) to concurrent transfusions of prestorage-leukoreduced (PreSLR) pooled platelets, poststorage-leukoreduced (PostSLR) pooled platelets, nonleukoreduced (NonLR) pooled platelets, and apheresis single-donor platelets (SDPs) to compare the rates of FNHTRs to PreSLR vs PostSLR pooled platelets. Reported transfusion reactions to platelets at 15 hospitals for a period of 45 months were retrospectively reviewed. Reaction rates to different types of platelet products were calculated and compared. During the study period, 70,015 platelet transfusions were administered. Among these, 152 (0.22%) FNHTRs and 111 (0.16%) allergic transfusion reactions were seen. Reported rates of FNHTRs were 0.07% (SDP), 0.16% (PreSLR), 0.30% (PostSLR), and 0.20% (NonLR) (P < .05 for PreSLR vs PostSLR). Rates of allergic reactions were 0.16% (SDP), 0.17% (PreSLR), 0.18% (PostSLR), and 0.11% (NonLR) (P > .05). The rates of reported FNHTRs were low for all types of platelet transfusions. SDPs and PreSLR pooled platelets were associated with a slightly lower rate of FNHTR compared with PostSLR pooled platelets.

Prenatal exposure to polycyclic aromatic hydrocarbons, benzo[a]pyrene-DNA adducts, and genomic DNA methylation in cord blood.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic environmental pollutants generated during incomplete combustion. After exposure and during metabolism, PAHs can form reactive epoxides that can covalently bind to DNA. These PAH-DNA adducts are established markers of cancer risk. PAH exposure has been associated with epigenetic alterations, including genomic cytosine methylation. Both global hypomethylation and hypermethylation of specific genes have been associated with cancer and other diseases in humans. Experimental evidence suggests that PAH-DNA adduct formation may preferentially target methylated genomic regions. Early embryonic development may be a particularly susceptible period for PAH exposure, resulting in both increased PAH-DNA adducts and altered DNA methylation. OBJECTIVE: We explored whether prenatal exposure to PAHs is associated with genomic DNA methylation in cord blood and whether methylation levels are associated with the presence of detectable PAH-DNA adducts. METHODS: In a longitudinal cohort study of nonsmoking women in New York City, we measured PAH exposure during pregnancy using personal air monitors, assessed PAH internal dose using prenatal urinary metabolites (in a subset), and quantified benzo[a]pyrene-DNA adducts and genomic DNA methylation in cord blood DNA among 164 participants. RESULTS: Prenatal PAH exposure was associated with lower global methylation in umbilical cord white blood cells (p = 0.05), but global methylation levels were positively associated with the presence of detectable adducts in cord blood (p = 0.01). CONCLUSIONS: These observations suggest that PAH exposure was adequate to alter global methylation in our study population. Additional epidemiologic studies that can measure site-specific cytosine methylation and adduct formation will improve our ability to understand this complex molecular pathway in vivo.

Thrombotic microangiopathy in transplantation and malignancy.

Thrombotic microangiopathy (TMA) after hematopoietic stem-cell transplantation (HSCT) or solid-organ transplantation is a serious complication that may be associated with diverse clinical conditions. The reported incidence varies widely, in part due to different diagnostic criteria. Currently, the diagnosis is based mostly on clinical features and is often uncertain; many disease or therapy-related complications in transplantation and malignancy can manifest clinical features of TMA. Risk factors for TMA post HSCT include the type of conditioning regimen, the presence graft-versus-host disease (GVHD), the use of calcineurin inhibitors (cyclosporine and tacrolimus) for GVHD prophylaxis, and infection. Cyclosporin and tacrolimus are the most commonly reported agents associated with TMA in solid-organ (mainly kidney) transplantations. Cancer-related TMA may be associated with chemotherapy or the malignancy itself. Compared with idiopathic TMA (thrombotic thrombocytopenic purpura), the outcome for patients with TMA post-HSCT or disseminated malignancy is poor. The efficacy of plasma exchange in the treatment of TMA post-HSCT or malignancy is uncertain. In the future, objective criteria integrating laboratory features (including tissue pathology, quantitative hematology, and endothelial cell functionality) with clinical features may assist in the diagnostic accuracy of TMA post HSCT, which would allow better evaluation of treatment modalities and better prediction of prognosis and outcomes.

Efficacy of Epstein-Barr virus removal by leukoreduction of red blood cells.

BACKGROUND: Epstein-Barr virus (EBV) infection results in life-long carriage of latent virus in B lymphocytes in the majority of the adult population, including blood donors. The removal of EBV from red blood cell (RBC) components by leukoreduction was assessed. STUDY DESIGN AND METHODS: Sixteen randomly selected fresh AS-5 units were leukoreduced by filtration. B lymphocytes from preleukoreduction specimens and mononuclear cells (MNCs) from postleukoreduction specimens were assayed for EBV DNA with sensitive real-time polymerase chain reaction (PCR). RESULTS: EBV genomes were detected in CD19+ B cells in 14 of 16 preleukoreduced RBC units. EBV genomic copy number in the units ranged from 0.18 to 96.84 per 10(5) B lymphocytes representing approximately 135 to 72,630 total EBV genomes per bag. Leukoreduction rendered all but one unit EBV-negative by PCR. The lone PCR-positive unit after leukoreduction amplified 1.2 EBV genome copies from MNCs recovered from the entire unit of leukoreduced RBCs; this unit had the highest EBV viral load before leukoreduction (72,630 EBV genomes). CONCLUSIONS: These results indicate that a 4-log reduction of EBV genomic copy number can be achieved with leukoreduction of RBC units and renders most RBC units EBV-negative by sensitive PCR.