bluuebunny/crossref_metadata_2025_split huggingface dataset:
FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia
Authors: Mead Adam J. , Linch David C. , Hills Robert K. , Wheatley Keith , Burnett Alan K. , Gale Rosemary E. 
Published: April 2007

Abstract
The prognostic impact of tyrosine kinase domain (TKD) mutations of the fms-like tyrosine kinase-3 (FLT3) gene in acute myeloid leukemia (AML) is currently uncertain. To resolve this issue we screened 1107 young adult nonacute promyelocytic leukemia AML patients with known FLT3 internal tandem duplication (ITD) status for FLT3/TKDs; they were detected in 127 (11%) cases. Mutations were associated with a high white cell count (P =.006) and patients with inv(16) (P = .005) but were infrequent in patients with adverse cytogenetics and secondary AML. Overall survival (OS) at 5 years was 53% and 37% for FLT3/TKD mutant and wild-type patients respectively (odds ratio, 0.72; 95% confidence interval, 0.58 to 0.89; P = .002). For both the cumulative incidence of relapse and OS the difference in outcome between FLT3/ITDs and FLT3/TKDs was highly significant (P < .001). In multivariate analysis, impact of FLT3/TKDs on OS when including all mutant-positive patients was not significant, but patients with high-level mutations (more than 25% mutant) had a significantly improved outcome (P = .004). The novel finding that biologically distinct activating mutations of the same gene can be associated with markedly different clinical outcomes has implications for risk stratification and therapy and is significant to the understanding of chemoresistance in AML.
Effects of age-dependent membrane transport changes on the homeostasis of senescent human red blood cells
Authors: Lew Virgilio L. , Daw Nuala , Etzion Zipora , Tiffert Teresa , Muoma Adaeze , Vanagas Laura , Bookchin Robert M. 
Published: April 2007

AbstractLittle is known about age-related changes in red blood cell (RBC) membrane transport and homeostasis. We investigated first whether the known large variation in plasma membrane Ca2+ (PMCA) pump activity was correlated with RBC age. Glycated hemoglobin, Hb A1c, was used as a reliable age marker for normal RBCs. We found an inverse correlation between PMCA strength and Hb A1c content, indicating that PMCA activity declines monotonically with RBC age. The previously described subpopulation of high-Na+, low-density RBCs had the highest Hb A1c levels, suggesting it represents a late homeostatic condition of senescent RBCs. Thus, the normal densification process of RBCs with age must undergo late reversal, requiring a membrane permeability increase with net NaCl gain exceeding KCl loss. Activation of a nonselective cation channel, Pcat, was considered the key link in this density reversal. Investigation of Pcat properties showed that its most powerful activator was increased intracellular Ca2+. Pcat was comparably selective to Na+, K+, choline, and N-methyl-D-glucamine, indicating a fairly large, poorly selective cation permeability pathway. Based on these observations, a working hypothesis is proposed to explain the mechanism of progressive RBC densification with age and of the late reversal to a low-density condition with altered ionic gradients.
A set of genes that regulate cell proliferation predicts treatment outcome in childhood acute lymphoblastic leukemia
Authors: Flotho Christian , Coustan-Smith Elaine , Pei Deqing , Cheng Cheng , Song Guangchun , Pui Ching-Hon , Downing James R. , Campana Dario 
Published: April 2007

AbstractTo identify novel predictors of outcome in childhood acute lymphoblastic leukemia (ALL), we analyzed gene expression in the leukemic cells of 187 children with newly diagnosed ALL and compared the findings with minimal residual disease (MRD) results obtained on day 19 of remission induction treatment. Genes that showed a significant relationship to MRD were then tested for their capacity to predict leukemic relapse in an independent cohort of 99 patients. We identified 674 probe sets that were associated with MRD on day 19 (P < .006); 40 of the identified genes predicted relapse (P < .03). Among these, 14 showed independent prognostic significance after adjustment for age, leukocyte count at diagnosis, and genetic subtype. More than half of the 40 genes and nearly all of the 14 genes were functionally related, as indicated by their roles in the regulation of cell proliferation. Underexpression of genes promoting cell proliferation was associated with resistance to chemotherapy. The biologic processes regulated by the genes we identified appear to be key determinants of the early cytoreductive response to remission induction therapy and subsequent clinical outcome in childhood ALL. Incorporation of the expression levels of these genes into existing strategies of risk classification could improve clinical management.
Developmental- and differentiation-specific patterns of human γ- and β-globin promoter DNA methylation
Authors: Mabaera Rodwell , Richardson Christine A. , Johnson Kristin , Hsu Mei , Fiering Steven , Lowrey Christopher H. 
Published: April 2007

AbstractThe mechanisms underlying the human fetal-to-adult β-globin gene switch remain to be determined. While there is substantial experimental evidence to suggest that promoter DNA methylation is involved in this process, most data come from studies in nonhuman systems. We have evaluated human γ- and β-globin promoter methylation in primary human fetal liver (FL) and adult bone marrow (ABM) erythroid cells. Our results show that, in general, promoter methylation and gene expression are inversely related. However, CpGs at −162 of the γ promoter and −126 of the β promoter are hypomethylated in ABM and FL, respectively. We also studied γ-globin promoter methylation during in vitro differentiation of erythroid cells. The γ promoters are initially hypermethylated in CD34+ cells. The upstream γ promoter CpGs become hypomethylated during the preerythroid phase of differentiation and are then remethylated later, during erythropoiesis. The period of promoter hypomethylation correlates with transient γ-globin gene expression and may explain the previously observed fetal hemoglobin production that occurs during early adult erythropoiesis. These results provide the first comprehensive survey of developmental changes in human γ- and β-globin promoter methylation and support the hypothesis that promoter methylation plays a role in human β-globin locus gene switching.
Epitope specificity and isotype of monoclonal anti-D antibodies dictate their ability to inhibit phagocytosis of opsonized platelets
Authors: Kjaersgaard Mimi , Aslam Rukhsana , Kim Michael , Speck Edwin R. , Freedman John , Stewart Donald I. H. , Wiersma Erik J. , Semple John W. 
Published: April 2007

AbstractRh immune globulin (WinRho SDF; Cangene, Mississauga, ON, Canada) is an effective treatment for autoimmune thrombocytopenic purpura; however, maintaining a sustained supply for its use in autoimmune thrombocytopenic purpura and its primary indication, hemolytic disease of the newborn, makes the development of alternative reagents desirable. We compared Rh immune globulin and 6 human monoclonal anti-D antibodies (MoAnti-D) with differing isotypes and specificities for their ability to opsonize erythrocytes and inhibit platelet phagocytosis in an in vitro assay. Results demonstrated that opsonization of erythrocytes with Rh immune globulin significantly (P < .001) reduced phagocytosis of fluorescently labeled opsonized platelets in an Fc-dependent manner. Of the MoAnti-D that shared specificity but differed in isotype, only IgG3 antibodies could significantly (P < .001) inhibit platelet phagocytosis. In contrast, 2 MoAnti-D shared isotypes and differed in specificity; however, only one could significantly (P < .001) inhibit platelet phagocytosis. The results suggest that MoAnti-D epitope specificity and isotypes are critical requirements for optimal inhibition of opsonized platelet phagocytosis.
G-protein-coupled receptor expression, function, and signaling in macrophages
Authors: Lattin Jane , Zidar David A , Schroder Kate , Kellie Stuart , Hume David A , Sweet Matthew J 
Published: April 2007

AbstractG-protein-coupled receptors (GPCRs) are widely targeted in drug discovery. As macrophages are key cellular mediators of acute and chronic inflammation, we review here the role of GPCRs in regulating macrophage function, with a focus on contribution to disease pathology and potential therapeutic applications. Within this analysis, we highlight novel GPCRs with a macrophage-restricted expression profile, which provide avenues for further exploration. We also review an emerging literature, which documents novel roles for GPCR signaling components in GPCR-independent signaling in macrophages. In particular, we examine the crosstalk between GPCR and TLR signaling pathways and highlight GPCR signaling molecules which are likely to have uncharacterized functions in this cell lineage.
Large defects of type I allergic response in telomerase reverse transcriptase knockout mice
Authors: Ujike-Asai Azusa , Okada Aki , Du Yuchen , Maruyama Mitsuo , Yuan Xunmei , Ishikawa Fuyuki , Motoo Yoshiharu , Isobe Kenichi , Nakajima Hideo 
Published: April 2007

AbstractTelomerase is critically important for the maintenance of a constant telomere length, which in turn, is related to the concepts of longevity and oncogenesis. In addition, it has been well documented that telomerase activity is expressed in immune cells in a highly regulated manner. We have studied systemic anaphylaxis in mouse telomerase reverse transcriptase knockout (mTERT−/−) mice to understand the significance of telomerase activity and telomere stability in mast cells, which induce a type I allergic response. Compared with wild-type mice, mTERT−/− mice displayed largely attenuated, IgE-mediated, passive anaphylactic responses, which were observed even in the early generations of mTERT−/− mice, and had decreased numbers of mast cells in vivo and impaired development of bone marrow-derived mast cells (BMMCs) induced by IL-3 or stem cell factor in vitro. Moreover, in mTERT−/− mice, BMMCs exhibited a large morphology and low proliferation rate, while they possessed a comparable degranulation capacity and cell surface expression level of c-kit and FcεRI. These findings imply that telomerase activity has a definitive impact on the type I allergic response by altering the character of effecter mast cells.
Increased Acute Myocardial Infarction Rates and Cardiovascular Risk Factors among Patients with Human Immunodeficiency Virus Disease
Authors: Triant Virginia A. , Lee Hang , Hadigan Colleen , Grinspoon Steven K. 
Published: April 2007

Abstract
Context: Metabolic changes and smoking are common among HIV patients and may confer increased cardiovascular risk.
Objective: The aim of the study was to determine acute myocardial infarction (AMI) rates and cardiovascular risk factors in HIV compared with non-HIV patients in two tertiary care hospitals.
Design, Setting, and Participants: We conducted a health care system-based cohort study using a large data registry with 3,851 HIV and 1,044,589 non-HIV patients. AMI rates were determined among patients receiving longitudinal care between October 1, 1996, and June 30, 2004.
Main Outcome Measures: The primary outcome was myocardial infarction, identified by International Classification of Diseases coding criteria.
Results: AMI was identified in 189 HIV and 26,142 non-HIV patients. AMI rates per 1000 person-years were increased in HIV vs. non-HIV patients [11.13 (95% confidence interval [CI] 9.58–12.68) vs. 6.98 (95% CI 6.89–7.06)]. The HIV cohort had significantly higher proportions of hypertension (21.2 vs. 15.9%), diabetes (11.5 vs. 6.6%), and dyslipidemia (23.3 vs. 17.6%) than the non-HIV cohort (P &lt; 0.0001 for each comparison). The difference in AMI rates between HIV and non-HIV patients was significant, with a relative risk (RR) of 1.75 (95% CI 1.51–2.02; P &lt; 0.0001), adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. In gender-stratified models, the unadjusted AMI rates per 1000 person-years were higher for HIV patients among women (12.71 vs. 4.88 for HIV compared with non-HIV women), but not among men (10.48 vs. 11.44 for HIV compared with non-HIV men). The RRs (for HIV vs. non-HIV) were 2.98 (95% CI 2.33–3.75; P &lt; 0.0001) for women and 1.40 (95% CI 1.16–1.67; P = 0.0003) for men, adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. A limitation of this database is that it contains incomplete data on smoking. Smoking could not be included in the overall regression model, and some of the increased risk may be accounted for by differences in smoking rates.
Conclusions: AMI rates and cardiovascular risk factors were increased in HIV compared with non-HIV patients, particularly among women. Cardiac risk modification strategies are important for the long-term care of HIV patients.
Newborn Screening for Congenital Adrenal Hyperplasia: Additional Steroid Profile using Liquid Chromatography-Tandem Mass Spectrometry
Authors: Janzen N. , Peter M. , Sander S. , Steuerwald U. , Terhardt M. , Holtkamp U. , Sander J. 
Published: April 2007

Abstract
Background: Neonatal screening programs for congenital adrenal hyperplasia (21-CAH) using an immunoassay for 17α-hydroxyprogesterone (17-OHP) generate a high rate of positive results attributable to physiological reasons and to cross-reactions with steroids other than 17α-OHP, especially in preterm neonates and in critically ill newborns.
Methods: To increase the specificity of the screening process, we applied a liquid chromatography-tandem mass spectrometry method quantifying 17α-OHP, 11-deoxycortisol, 21-deoxycortisol, cortisol, and androstenedione. The steroids were eluted in aqueous solution containing d8-17α-OHP and d2-cortisol and quantified in multiple reaction mode.
Results: Detection limit was below 1 nmol/liter, and recovery ranged from 64% (androstenedione) to 83% (cortisol). Linearity was proven within a range of 5–100 nmol/liter (cortisol, 12.5–200 nmol/liter), and total run time was 6 min. Retrospective analysis of 6151 blood samples and 50 blood samples from newborns with clinically confirmed 21-CAH, as well as prospective analysis of 1609 samples of a total of 242,500 testing positive in our routine 17-OHP immunoassay, allowed clear distinction of affected and nonaffected newborns. High levels of 21-deoxycortisol were only found in children with 21-hydroxylase deficiency. Calculating the ratio of 17α-OHP to 21-deoxycortisol divided by cortisol further increased the sensitivity of the method.
Conclusion: Our liquid chromatography-tandem mass spectrometry procedure as a second-tier test can be used to reduce false-positive results of standard 21-CAH screening. The short total run time of 6 min allows for immediate reanalysis of all immunoassay results above the cutoff.
Serum Estrogen, But Not Testosterone, Levels Differ between Black and White Men in a Nationally Representative Sample of Americans
Authors: Rohrmann Sabine , Nelson William G. , Rifai Nader , Brown Terry R. , Dobs Adrian , Kanarek Norma , Yager James D. , Platz Elizabeth A. 
Published: April 2007

Abstract
Context: Higher testosterone in black compared with white men has been postulated to explain their higher prostate cancer incidence. Previous studies comparing hormone levels by race might have been limited by size, restricted age variation, or lack of representation of the general population.
Objective: Our objective was to compare serum testosterone, estradiol, and SHBG concentrations among non-Hispanic black, non-Hispanic white, and Mexican-American men.
Participants, Design, and Setting: A total of 1413 men aged 20+ yr and who attended the morning examination session of the Third National Health and Nutrition Examination Survey (NHANES III) in 1988–1991 were included in this cross-sectional study.
Measurement: Serum hormone concentrations were measured by electrochemiluminescence immunoassays.
Results: After applying sampling weights and adjusting for age, percent body fat, alcohol, smoking, and activity, testosterone concentrations were not different between non-Hispanic blacks (n = 363; geometric mean, 5.29 ng/ml) and non-Hispanic whites (n = 674; 5.11 ng/ml; P &gt; 0.05) but were higher in Mexican-Americans (n = 376; 5.48 ng/ml; P &lt; 0.05). Non-Hispanic blacks (40.80 pg/ml) had a higher estradiol concentration than non-Hispanic whites (35.46 pg/ml; P &lt; 0.01) and Mexican-Americans (34.11 pg/ml; P &lt; 0.01). Non-Hispanic blacks (36.49 nmol/liter) had a higher SHBG concentration than non-Hispanic whites (34.91 nmol/liter; P &lt; 0.05) and Mexican-Americans (35.04 nmol/liter; P &lt; 0.05).
Conclusions: Contrary to the postulated racial difference, testosterone concentrations did not differ notably between black and white men. However, blacks had higher estradiol levels. Mexican-Americans had higher testosterone than whites but similar estradiol and SHBG concentrations. Given these findings, it may be equally if not more important to investigate estradiol as testosterone in relation to diseases with racial disparity.
Dynorphin Knockout Reduces Fat Mass and Increases Weight Loss during Fasting in Mice
Authors: Sainsbury Amanda , Lin Shu , McNamara Keely , Slack Katy , Enriquez Ronaldo , Lee Nicola J. , Boey Dana , Smythe George A. , Schwarzer Christoph , Baldock Paul , Karl Tim , Lin En-Ju D. , Couzens Michelle , Herzog Herbert 
Published: April 2007

AbstractEndogenous opioids, particularly dynorphins, have been implicated in regulation of energy balance, but it is not known how they mediate this in vivo. We investigated energy homeostasis in dynorphin knockout mice (Dyn−/− mice) and probed the interactions between dynorphins and the neuropeptide Y (NPY) system. Dyn−/− mice were no different from wild types with regards to body weight and basal and fasting-induced food intake, but fecal output was increased, suggesting decreased nutrient absorption, and they had significantly less white fat and lost more weight during a 24-h fast. The neuroendocrine and thermal responses to fasting were at least as pronounced in Dyn−/− as in wild types, and there was no stimulatory effect of dynorphin knockout on 24-h energy expenditure (kilocalories of heat produced) or physical activity. However, Dyn−/− mice showed increased circulating concentrations of 3,4-dihydroxyphenlacetic acid and 3,4-dihydroxyphenylglycol, suggesting increased activity of the sympathetic nervous system. The respiratory exchange ratio of male but not female Dyn−/− mice was reduced, demonstrating increased fat oxidation. Interestingly, expression of the orexigenic acting NPY in the hypothalamic arcuate nucleus was reduced in Dyn−/− mice. However, fasting-induced increases in pre-prodynorphin expression in the arcuate nucleus, the paraventricular nucleus, and the ventromedial hypothalamus but not the lateral hypothalamus were abolished by deletion of Y1 but not Y2 receptors. Therefore, ablation of dynorphins results in increases in fatty acid oxidation in male mice, reductions in adiposity, and increased weight loss during fasting, possibly via increases in sympathetic activity, decreases in intestinal nutrient absorption, and interactions with the NPYergic system.
Automated data processing and metric generation for driveability analysis
Authors: Pickering S G , Brace C J 
Published: April 2007

This paper describes automated data-processing and manoeuvre detection techniques developed as part of a suite of tools used for the prediction of longitudinal vehicle driveability. The core task is to identify events of interest in recorded objective driveability time-series data and generate metrics describing these manoeuvres, which can then be correlated with subjective evaluations provided by the vehicle test drivers. The objective events of particular interest are the start of transients and gear-shift events. As a necessary precursor to the generation of the objective metrics, procedures were designed to check data integrity and to automatically replace data that were found to be faulty, ensuring that as few data points and as little testing time were wasted as is possible. Of 741 tests analysed (average of 12 drivers for each of five vehicles), only 11 per cent of tests needed further manual attention following the automated processing. Of these, 64 per cent proved to be irrecoverable owing to data problems and were rejected. The processing and generation of metrics take approximately 1 s per set of test data, producing a time saving of approximately 95 per cent. This makes it possible to perform real-time processing and metric generation as part of a continuous testing scheme or real-time evaluation.
Managing Complex Medication Regimens: Perspectives of Consumers with Osteoarthritis and Healthcare Professionals
Authors: Manias Elizabeth , Claydon-Platt Kate , Mccoll Geoffrey J , Bucknall Tracey K , Brand Caroline A 
Published: April 2007

Background: Managing medications is complex, particularly for consumers with multiple coexisting conditions for whom benefits and adverse effects are unpredictable and health priorities may be variable. Objective: To investigate perceptions of and experiences with managing drug regimens from the perspectives of consumers with osteoarthritis and coexisting chronic conditions and of healthcare professionals from diverse backgrounds. Methods: Using an exploratory research design, focus groups were formed with 34 consumers and 19 healthcare professionals. Individual interviews were undertaken with 3 community medical practitioners. Results: Consumers' management of medications was explored in terms of 3 themes: administration of medications, provision of information, and the perceived role of healthcare professionals. In general, consumers lacked understanding regarding the reason that they were prescribed certain medications. Since all consumer participants had at least 2 chronic conditions, they were taking many drugs to relieve undesirable symptoms. Some consumers were unable to achieve improved pain relief and were reluctant to take analgesics prescribed on an as needed basis. Healthcare professionals discussed the importance of using nonpharmacologic measures to improve symptoms; however, consumers stated that physicians encourage them to continue using medications, often for prolonged periods, even when these agents are not helpful. Conclusions: Consumers were dissatisfied about the complexity of their medication regimens and also lacked understanding as to how to take their drugs effectively. Dedicated time should be devoted during medical consultations to facilitate verbal exchange of information about medications. Pharmacists must communicate regularly with physicians about consumers' medication needs to help preempt any problems that may arise. Instructions need to be revised through collaboration between physicians and pharmacists so that “as needed” directions provide more explicit advice about when and how to use such drugs. Future research, using large, generalizable samples, should examine trends related to consumers' experiences of symptomatic relief from chronic conditions and their understandings about medications.