Home About us Contact
|
Home About us Contact | ||
|
|
||
Time Dependent (time + dependent)
Terms modified by Time Dependent Selected AbstractsDifferential inhibition in vivo of ammonia monooxygenase, soluble methane monooxygenase and membrane-associated methane monooxygenase by phenylacetyleneENVIRONMENTAL MICROBIOLOGY, Issue 5 2000Sonny Lontoh Phenylacetylene was investigated as a differential inhibitor of ammonia monooxygenase (AMO), soluble methane monooxygenase (sMMO) and membrane-associated or particulate methane monooxygenase (pMMO) in vivo. At phenylacetylene concentrations >,1 µM, whole-cell AMO activity in Nitrosomonas europaea was completely inhibited. Phenylacetylene concentrations above 100 µM inhibited more than 90% of sMMO activity in Methylococcus capsulatus Bath and Methylosinus trichosporium OB3b. In contrast, activity of pMMO in M. trichosporium OB3b, M. capsulatus Bath, Methylomicrobium album BG8, Methylobacter marinus A45 and Methylomonas strain MN was still measurable at phenylacetylene concentrations up to 1000 µM. AMO of Nitrosococcus oceanus has more sequence similarity to pMMO than to AMO of N. europaea. Correspondingly, AMO in N. oceanus was also measurable in the presence of 1000 µM phenylacetylene. Measurement of oxygen uptake indicated that phenylacetylene acted as a specific and mechanistic-based inhibitor of whole-cell sMMO activity; inactivation of sMMO was irreversible, time dependent, first order and required catalytic turnover. Corresponding measurement of oxygen uptake in whole cells of methanotrophs expressing pMMO showed that pMMO activity was inhibited by phenylacetylene, but only if methane was already being oxidized, and then only at much higher concentrations of phenylacetylene and at lower rates compared with sMMO. As phenylacetylene has a high solubility and low volatility, it may prove to be useful for monitoring methanotrophic and nitrifying activity as well as identifying the form of MMO predominantly expressed in situ. [source] Clinical Pharmacokinetics of FrovatriptanHEADACHE, Issue 2002P. Buchan PhD Objective.,To review available data on the clinical pharmacokinetics of frovatriptan. Background.,Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from that of the currently available triptans. Methods.,Studies of healthy volunteers, subjects with renal or hepatic impairment, elderly subjects, and patients with migraine during and between attacks were reviewed. Results.,Oral bioavailability of frovatriptan is 22% to 30%, and although the time to maximum concentration is typically 2 to 3 hours, approximately 60% to 70% of plasma maximum concentration is achieved within 1 hour of dosing. Frovatriptan distributes into erythrocytes, with binding reversible and time dependent. The relatively long terminal elimination half-life (about 26 hours) confers good systemic exposure and may produce a long duration of therapeutic action, thus reducing migraine recurrence and the need for redosing. Systemic exposure to frovatriptan generally correlates with dose between 1 and 100 mg. Blood and plasma frovatriptan concentrations are consistently higher in females, but there is no need to adjust dose according to gender. Pharmacokinetics are essentially unaffected by food and were predictable after repeat dosing; steady state is approached in about 4 to 5 days. Pharmacokinetics were changed only slightly in subjects with renal impairment or mild-to-moderate hepatic impairment, elderly individuals, and during migraine attacks. Frovatriptan is principally metabolized by the CYP1A2 isoenzyme of cytochrome P-450 and is cleared by the kidney and liver, each having sufficient capacity to compensate for impairment of the other. Conclusions.,Frovatriptan can be taken without regard for food intake, and because of the large therapeutic margin and shallow dose-response curve, there is no need for dosage adjustment in the elderly, in women taking a combined oral contraceptive, in patients with mild-to-severe renal impairment, mild-to-moderate hepatic impairment, or according to gender. The long duration of exposure may reduce the likelihood of early migraine recurrence. [source] Trends in timing of low stream flows in Canada: impact of autocorrelation and long-term persistenceHYDROLOGICAL PROCESSES, Issue 8 2010Eghbal Ehsanzadeh Abstract The annual timing of river flows might indicate changes that are climate related. In this study, trends in timing of low flows for the Reference Hydrometric Basin Network were investigated under three different hypotheses namely: independence, short-term persistence (STP) and long-term persistence (LTP). Both summer and winter time series were characterized with scaling behaviour providing strong evidence of LTP. The Mann,Kendall trend test was modified to account for STP and LTP, and used to detect trends in timing of low flows. It was found that considering STP and LTP resulted in a significant decrease in the number of detected trends. Numerical analysis showed that the timing of summer 7-day low flows exhibited significant trends in 16, 9 and 7% of stations under independence, STP and LTP assumptions, respectively. Timing of summer low flow shifted toward later dates in western Canada, whereas the majority of stations in the east half of the country (except Atlantic Provinces) experienced a shift toward earlier dates. Timing of winter low flow experienced significant trends in 20, 12, and 6% of stations under independence, STP and LTP assumptions, respectively. Shift in timing of winter low flow toward earlier dates was dominant all over the country where it shifted toward earlier dates in up to 3/4 of time series with significant trends. There are local patterns of upward significant/insignificant trends in southeast, southwest and northern Canada. This study shows that timing of low flows in Canada is time dependent; however, addressing the full complexity of memory properties (i.e. short term vs long term) of a natural process is beyond the scope of this study. Copyright © 2009 John Wiley & Sons, Ltd. [source] Assessment of rainfall-runoff models based upon wavelet analysisHYDROLOGICAL PROCESSES, Issue 5 2007Stuart N. Lane Abstract A basic hypothesis is proposed: given that wavelet-based analysis has been used to interpret runoff time-series, it may be extended to evaluation of rainfall-runoff model results. Conventional objective functions make certain assumptions about the data series to which they are applied (e.g. uncorrelated error, homoscedasticity). The difficulty that objective functions have in distinguishing between different realizations of the same model, or different models of the same system, is that they may have contributed in part to the occurrence of model equifinality. Of particular concern is the fact that the error present in a rainfall-runoff model may be time dependent, requiring some form of time localization in both identification of error and derivation of global objective functions. We explore the use of a complex Gaussian (order 2) wavelet to describe: (1) a measured hydrograph; (2) the same hydrograph with different simulated errors introduced; and (3) model predictions of the same hydrograph based upon a modified form of TOPMODEL. The analysis of results was based upon: (a) differences in wavelet power (the wavelet power error) between the measured hydrograph and both the simulated error and modelled hydrographs; and (b) the wavelet phase. Power difference and wavelet phase were used to develop two objective functions, RMSE(power) and RMS(phase), which were shown to distinguish between simulated errors and model predictions with similar values of the commonly adopted Nash-Sutcliffe efficiency index. These objective functions suffer because they do not retain time, frequency or time-frequency localization. Consideration of wavelet power spectra and time- and frequency-integrated power spectra shows that the impacts of different types of simulated error can be seen through retention of some localization, especially in relation to when and the scale over which error was manifest. Theoretical objections to the use of wavelet analysis for this type of application are noted, especially in relation to the dependence of findings upon the wavelet chosen. However, it is argued that the benefits of localization and the qualitatively low sensitivity of wavelet power and phase to wavelet choice are sufficient to warrant further exploration of wavelet-based approaches to rainfall-runoff model evaluation. Copyright © 2006 John Wiley & Sons, Ltd. [source] Two-dimensional prediction of time dependent, turbulent flow around a square cylinder confined in a channelINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN FLUIDS, Issue 11 2010M. Raisee Abstract This paper presents two-dimensional and unsteady RANS computations of time dependent, periodic, turbulent flow around a square block. Two turbulence models are used: the Launder,Sharma low-Reynolds number k,, model and a non-linear extension sensitive to the anisotropy of turbulence. The Reynolds number based on the free stream velocity and obstacle side is Re=2.2×104. The present numerical results have been obtained using a finite volume code that solves the governing equations in a vertical plane, located at the lateral mid-point of the channel. The pressure field is obtained with the SIMPLE algorithm. A bounded version of the third-order QUICK scheme is used for the convective terms. Comparisons of the numerical results with the experimental data indicate that a preliminary steady solution of the governing equations using the linear k,, does not lead to correct flow field predictions in the wake region downstream of the square cylinder. Consequently, the time derivatives of dependent variables are included in the transport equations and are discretized using the second-order Crank,Nicolson scheme. The unsteady computations using the linear and non-linear k,, models significantly improve the velocity field predictions. However, the linear k,, shows a number of predictive deficiencies, even in unsteady flow computations, especially in the prediction of the turbulence field. The introduction of a non-linear k,, model brings the two-dimensional unsteady predictions of the time-averaged velocity and turbulence fields and also the predicted values of the global parameters such as the Strouhal number and the drag coefficient to close agreement with the data. Copyright © 2009 John Wiley & Sons, Ltd. [source] Nonadiabatic evolution of electronic states by electron nuclear dynamics theoryINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 5 2005Frank Hagelberg Abstract The problem of how to determine the nonadiabatic content of any given dynamic process involving molecular motion is addressed in the context of Electron Nuclear Dynamics (END) theory. Specifically, it is proposed to cast the dynamic END wave function into the language of static electronic configurations with time dependent complex-valued amplitudes. This is achieved by adiabatic transport of an electronic basis along the classical nuclear trajectories of the studied molecular system, as yielded by END simulation. Projecting the dynamic wave function on this basis yields a natural distinction between adiabatic and nonadiabatic components of the motion considered. Tracing the evolution of the leading configurations is shown to be a helpful device for clarifying the physical nature of electronic excitation processes. For illustration of these concepts, dynamic configuration analysis is applied to the scattering of a proton by a lithium atom. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005 [source] Inhibition of apoptosis by progesterone in cardiomyocytesAGING CELL, Issue 5 2010Stephen Morrissy Summary While gender-based differences in heart disease have raised the possibility that estrogen (ES) or progesterone (PG) may have cardioprotective effects, recent controversy regarding hormone replacement therapy has questioned the cardiac effects of these steroids. Using cardiomyocytes, we tested whether ES or PG has protective effects at the cellular level. We found that PG but not ES protects cardiomyocytes from apoptotic cell death induced by doxorubicin (Dox). PG inhibited apoptosis in a dose-dependent manner, by 12 ± 4.0% at 1 ,m and 60 ± 1.0% at 10 ,m. The anti-apoptotic effect of PG was also time dependent, causing 18 ± 5% or 62 + 2% decrease in caspase-3 activity within 1 h or 72 h of pretreatment. While PG causes nuclear translocation of its receptor within 20 min, the cytoprotective effect of PG was canceled by mifepristone (MF), a PG receptor antagonist. Analyses using Affymetrix high-density oligonucleotide array and RT-PCR found that PG induced Bcl-xL, metallothionine, NADPH quinone oxidoreductase 1, glutathione peroxidase-3, and four isoforms of glutathione S-transferase. Western blot analyses revealed that PG indeed induced an elevation of Bcl-xL protein in a dose- and time-dependent manner. Nuclear run-on assay indicated that PG induced Bcl-xL gene transcription. Inhibiting the expression of Bcl-xL using siRNA reduced the cytoprotective effect of PG. Our data suggests that PG induces a cytoprotective effect in cardiomyocytes in association with induction of Bcl-xL gene. [source] Effectiveness of a Multidisciplinary Quality Improvement Initiative in Reducing Door-to-Balloon Times in Primary AngioplastyJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 4 2004F.A.C.C., STUART W. ZARICH M.D. Primary angioplasty (PA) for acute myocardial infarction (AMI) has emerged as the standard of care in hospitals with cardiac interventional facilities. The benefits from the PA are time dependent, but recent data raise concerns regarding the timeliness of delivery of care in AMI and the level of benefit achieved by current standards. We assessed the effectiveness of an extensive multidisciplinary quality improvement initiative in reducing door-to-balloon (DTB) times in PA. The PA process was divided into six separate time periods, which were assessed individually. Subsequent quality initiatives resulted in a dramatic reduction in the mean DTB time (141.3 minutes preintervention compared to 95.1 minutes postintervention; P < 0.001). [source] Chronic Intermittent Ethanol Exposure During Adolescence Blocks Ethanol-Induced Inhibition of Spontaneously Active Hippocampal Pyramidal NeuronsALCOHOLISM, Issue 1 2006Sayaka Tokunaga Background: Binge alcohol drinking among adolescents has been a serious public health problem. A model of binge alcohol, chronic intermittent ethanol exposure (CIEE), during adolescence significantly attenuates ethanol-induced spatial memory deficits in rats. However, the attenuation was absent following a 12-day ethanol-free period. Since spatial memory is hippocampal dependent, a reduction in ethanol-induced spatial memory impairments may be due to a reduction in the ability of ethanol to inhibit the firing rate of single hippocampal pyramidal neurons following CIEE. Methods: Beginning on postnatal day 30 (P30), male adolescent Sprague-Dawley rats (Harlan) were administered 5.0 g/kg ethanol (n=10, CIEE-treated group) or an equivolume saline (n=10, CISE-treated group) every 48 hours for 20 days. Single hippocampal pyramidal neurons from 5 CIEE-treated rats and 5 CISE-treated rats were recorded on the day following completion of the chronic intermittent exposure procedure (animals now P50). Additionally, neurons from 5 CIEE-treated rats and 5 CISE-treated rats were recorded 12 days after the completion of the chronic intermittent exposure procedure (animals now P62). Results: Ethanol exposure during adolescence completely blocked ethanol-induced inhibition of hippocampal pyramidal neurons in rats that were CIEE exposed. However, the effect of CIEE on hippocampal neurophysiology was time dependent. Specifically, neurons recorded from CIEE-treated rats after a 12-day ethanol-free period had similar maximal inhibition as neurons from CISE-treated animals, although the time to reach inhibition was significantly greater in neurons from CIEE-treated rats. Conclusion: Chronic ethanol exposure during adolescence produces a reduction, or tolerance, to ethanol-induced inhibition of hippocampal pyramidal neural activity. Although the tolerance was greatly reversed after a 12-day ethanol-free period, neurons from CIEE animals inhibited slower than neurons from CISE animals. Since the hippocampus is known to be involved not only in spatial memory, but also in many other types of memory formation, the altered hippocampal functions because of CIEE during adolescence should be taken as a serious warning for society. [source] Have studies of urinary tract infection and preterm delivery used the most appropriate methods?PAEDIATRIC & PERINATAL EPIDEMIOLOGY, Issue 3 2003Marie S. O'Neill Summary Published investigations of the association between urinary tract infection (UTI) and preterm delivery used logistic regression or chi-squared tests. Because both exposure and outcome are time dependent, these methods were not optimal and did not account for person,time under observation, potentially an important feature given the variability of women's entry to prenatal care as well as of gestational lengths. Previous researchers probably classified as exposed some women whose UTI occurred after their pregnancies exceeded 37 weeks. We applied the previous analytical methods to 1990,93 births from two Durham, NC, USA, hospitals (n = 4053) and demonstrate survival methods as an alternative. Two logistic regression models were fitted with differing exposure definitions: model 1 in which exposed = UTI diagnosed after 20 weeks' gestation; and model 2 in which exposed = UTI diagnosed between 20 weeks' and 37 weeks' gestation. Model 3 used proportional hazards regression with person,time after 20 weeks and before UTI diagnosis as unexposed, and person,time after diagnosis as exposed. Models were fit with and without five time-constant potential confounders. Model 1 yielded an adjusted odds ratio (OR) of 0.8 [95% confidence interval (CI) 0.5, 1.2], and model 2, which did not include UTI diagnoses after 37 weeks, an adjusted OR of 0.9 [95% CI 0.6, 1.4]. The Cox model hazard ratio (HR) for preterm delivery was 1.1 (adjusted) [95% CI 0.7, 1.7]. As these results indicated some bias, but not remarkable differences, we conducted a sensitivity analysis using 100 samples of 80% of the original data set, with replacement to determine how large the differences might be in other, similar data sets. The Cox method consistently produced higher effect estimates than either logistic model. The two samples with the greatest differences between the Cox and logistic model estimates yielded an OR of 1.47 [95% CI 0.95, 2.29] for model 1 vs. HR of 2.06 [95% CI 1.39, 3.06] for model 3, and an OR of 1.41 [95% CI 0.88, 2.25] for model 2 vs. HR of 1.79 [95% CI 1.17, 2.71] for model 3 respectively. Previous published results on UTI and preterm delivery require cautious interpretation. Data on UTI timing should be gathered to allow appropriate analyses; survival methods account for person,time under observation and ensure that studied exposures precede effects. [source] Mechanism of thermal degradation in GaInN/GaN quantum wellsPHYSICA STATUS SOLIDI (C) - CURRENT TOPICS IN SOLID STATE PHYSICS, Issue S2 2009H. Bremers Abstract In this contribution we focus on degradation processes of GaInN multiple quantum wells (MQWs) used in laser structures grown by metallorganic vapor pressure epitaxy (MOVPE). The influence of ramp-up time as well as the maximum temperature during growth of the barrier on the quantum well (QW) is investigated. Comparison of X-ray and photoluminescence (PL) measurements implies that a sufficient thickness of a cover layer grown at low temperature is required to prevent degradation of the QW. In a next step samples were grown using an optimal thermal budget during growth of the active region to investigate the influence of capping layers. To improve crystalline quality of these layers high temperatures are required. Our measurements show that these high temperatures lead to a decrease in average indium concentration of the QWs. This decrease is temperature as well as time dependent (, ,t) and can only explained by diffusion processes. The activation energies are in the range 0.7-0.9 eV (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Central nervous system effects of natural and synthetic glucocorticoidsPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 5 2009Pierluigi Fietta MD Natural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress, involving almost all organs and tissues, including brain. Since their therapeutic availability, synthetic GC (SGC) have been successfully prescribed for a variety of diseases. Mounting evidence, however, demonstrated pleiotropic adverse effects (AE), including central nervous system (CNS) disturbances, which are often misdiagnosed or underestimated. The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC. A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database. Cortisolemia plays a crucial role in control of behavior, cognition, mood, and early life programming of stress reactivity. Hypercortisolemia or SGC treatments may induce behavioral, psychic and cognitive disturbances, due to functional and, over time, structural alterations in specific brain target areas. These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses <20 mg/day) and usually reversible. Pediatric patients are particularly susceptible. Behavioral changes, including feeding and sleeping modifications, are common. Psychic AE are unpredictable and heterogeneous, usually mild/moderate, severe in 5,10% of cases. Manic symptoms have been mostly associated with short SGC courses, and depressive disorder with long-term treatments. Suicidality has been reported. Cognitive AE peculiarly affect declarative memory performance. Physiologic levels of NGC are essential for efficient brain functions. Otherwise, hypercortisolemia and SGC treatments may cause dose-/time-dependent neuropsychic AE and, over time, structural alterations in brain target areas. Clinicians should carefully monitor patients, especially children and/or when administering high doses SGC. [source] Reversal of plasticity-like effects in the human motor cortexTHE JOURNAL OF PHYSIOLOGY, Issue 19 2010Ying-Zu Huang A number of experiments in animals have shown that successful induction of plasticity can be abolished if an individually ineffective intervention is given shortly afterwards. Such effects are termed depotentiation/de-depression. These effects contrast with metaplasticity/homeostatic plasticity in which pretreatment of the system with one protocol modulates the response to a second plasticity-inducing protocol. Homeostatic plasticity maintains the balance of plasticity in the nervous system at a stable level whereas depotentiation/de-depression abolishes synaptic plasticity that has just occurred in order to prevent ongoing learning. In the present study, we developed novel protocols to explore the reversal of LTP- and LTD-like effects in healthy conscious humans based on the recently developed theta burst form of repetitive transcranial magnetic stimulation (TBS). The potentiation effect induced by intermittent TBS (iTBS) was completely erased by a short form of continuous TBS (cTBS150) given 1 min after iTBS, whereas the depressive effect of continuous TBS (cTBS) was successfully abolished by a short form of iTBS (iTBS150). The reversal was specific to the nature of the second protocol and was time dependent since it was less effective when the intervention was given 10 min after induction of plasticity. All these features are compatible with those of depotentiation and de-depression demonstrated in animal studies. The development of the present protocols would be helpful to study the physiology of the reversal of plasticity and learning and to probe the abnormal depotentiation/de-depression shown in animal models of neurological diseases (e.g. Parkinson's disease with dyskinesia, dystonia and Huntingon's disease). [source] FOXP3 Expression in Human Kidney Transplant Biopsies Is Associated with Rejection and Time Post Transplant but Not with Favorable OutcomesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2008S. Bunnag Expression of the transcription factor forkhead box P3 (FOXP3) in transplant biopsies is of interest due to its role in a population of regulatory T cells. We analyzed FOXP3 mRNA expression using RT-PCR in 83 renal transplant biopsies for cause in relationship to histopathology, clinical findings and expression of pathogenesis-based transcript sets assessed by microarrays. FOXP3 mRNA was higher in rejection (T-cell and antibody-mediated) than nonrejection. Surprisingly, some native kidney controls also expressed FOXP3 mRNA. Immunostaining for FOXP3 was consistent with RT-PCR, showing interstitial FOXP3+ lymphocytes, even in some native kidney controls. FOXP3 expression correlated with interstitial inflammation, tubulitis, interstitial fibrosis, tubular atrophy, C4d positivity, longer time posttransplant, younger donors, class II panel reactive antibody >20% and transcript sets reflecting inflammation and injury, but unlike these features was time dependent. In multivariate analysis, higher FOXP3 mRNA was independently associated with rejection, T-cell-associated transcripts, younger donor age and longer time posttransplant. FOXP3 expression did not correlate with favorable graft outcomes, even when the analysis was restricted to biopsies with rejection. Thus FOXP3 mRNA expression is a time-dependent feature of inflammatory infiltrates in renal tissue. We hypothesize that time-dependent entry of FOXP3-positive cells represents a mechanism for stabilizing inflammatory sites. [source] Impact of Hyperthermal Rotary Blood Pump Surfaces on Blood Clotting Behavior: An ApproachARTIFICIAL ORGANS, Issue 9 2009Kathrin F. Hamilton Abstract The influence of heat dissipating systems, such as rotary blood pumps, was investigated. Titanium cylinders as rotary blood pump housing dummies were immersed in porcine blood and constantly tempered at specific temperatures (37,60°C) over a defined period of time. The porcine blood was anticoagulated either by low heparin dosage or citrate. At frequent intervals, samples were taken for blood analysis and the determination of the plasmatic coagulation cascade. Blood parameters do not alter at surface temperatures below 50°C. Hyperthermia-induced hemolysis could be confirmed. The plasmatic coagulation cascade is terminated at surface temperatures exceeding 55°C. The adhesion of blood constituents on surfaces is temperature and time dependent, and structural changes of adhesions and blood itself were detected. [source] Rapid rotation, active nests of convection and global-scale flows in solar-likestarsASTRONOMISCHE NACHRICHTEN, Issue 10 2007B.P. Brown Abstract In the solar convection zone, rotation couples with intensely turbulent convection to build global-scale flows of differential rotation and meridional circulation. Our sun must have rotated more rapidly in its past, as is suggested by observations of many rapidly rotating young solar-type stars. Here we explore the effects of more rapid rotation on the patterns of convection in such stars and the global-scale flows which are self-consistently established. The convection in these systems is richly time dependent and in our most rapidly rotating suns a striking pattern of spatially localized convection emerges. Convection near the equator in these systems is dominated by one or two patches of locally enhanced convection, with nearly quiescent streaming flow in between at the highest rotation rates. These active nests of convection maintain a strong differential rotation despite their small size. The structure of differential rotation is similar in all of our more rapidly rotating suns, with fast equators and slower poles. We find that the total shear in differential rotation, as measured by latitudinal angular velocity contrast, ,,, increases with more rapid rotation while the relative shear, ,,/,, decreases. In contrast, at more rapid rotation the meridional circulations decrease in both energy and peak velocities and break into multiple cells of circulation in both radius and latitude. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Statistical Issues Arising in the Women's Health InitiativeBIOMETRICS, Issue 4 2005Ross L. Prentice Summary A brief overview of the design of the Women's Health Initiative (WHI) clinical trial and observational study is provided along with a summary of results from the postmenopausal hormone therapy clinical trial components. Since its inception in 1992, the WHI has encountered a number of statistical issues where further methodology developments are needed. These include measurement error modeling and analysis procedures for dietary and physical activity assessment; clinical trial monitoring methods when treatments may affect multiple clinical outcomes, either beneficially or adversely; study design and analysis procedures for high-dimensional genomic and proteomic data; and failure time data analysis procedures when treatment group hazard ratios are time dependent. This final topic seems important in resolving the discrepancy between WHI clinical trial and observational study results on postmenopausal hormone therapy and cardiovascular disease. [source] Time-Dependent ROC Curves for Censored Survival Data and a Diagnostic MarkerBIOMETRICS, Issue 2 2000Patrick J. Heagerty Summary. ROC curves are a popular method for displaying sensitivity and specificity of a continuous marker, X, for a binary disease variable, D. However, many disease outcomes are time dependent, D(t, and ROC curves that vary as a function of time may be mire appropriate. A common examples of a time-dependent variable is vital status, where D(t) = 1 if a patient has died prior to time t and zero otherwise. We propose summarizing the discrimination potential of a marker X, measured at baseline (t= 0), by calculating ROC Curves for cumulative disease or death incidence by time t, which we denote as ROC(t). A typical complexity with survival data is that observations may be censored. Two ROC curve estimators are proposed that can accommodate censored data. A simple estimator is based on using the Kaplan-Meier estimated for each possible subset X > c. However, this estimator does not guarantee the necessary condition that sensitivity and specificity are monotone in X. An alternative estimator that does guarantee monotonicity is based on a nearest neighbor estimator for the bivariate distribution function of (X, T), where T represents survival time (Akritas, M. J., 1994, Annals of Statistics22, 1299,1327). We present an example where ROC(t) is used to compare a standard and a modified flow cytometry measurement for predicting survival after detection of breast cancer and an example where the ROC(t) curve displays the impact of modifying eligibility criteria for sample size and power in HIV prevention trials. [source] Abnormal LTC4 synthase RNA degradation in neutrophils from CML patientsBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2004Cecilia Roos Summary Neutrophils from patients with chronic myeloid leukaemia (CML) have an aberrant expression of leukotriene (LT)C4 synthase. In order to learn more about the regulation of this abnormality, LTC4 synthase mRNA expression was determined by reverse transcription polymerase chain reaction. A digoxigenin (DIG)-labelled LTC4 synthase RNA was synthesized and incubated in cytsolic extracts from CML neutrophils, normal neutrophils and eosinophils. LTC4 synthase mRNA was detected in total but not cytoplasmic RNA from normal neutrophils. In contrast, LTC4 synthase mRNA was found in the cytoplasm of CML neutrophils and in normal eosinophils, which also express the enzyme. The DIG-labelled LTC4 synthase RNA was, as opposed to normal neutrophils, degraded in cytosolic extracts from CML neutrophils. The degradation was time dependent and cell concentration dependent. Degradation was also seen in eosinophils, indicating that degradation of LTC4 synthase RNA was correlated to the expression of the protein. This study showed that the difference in expression of LTC4 synthase in normal and CML neutrophils was not because of a total lack of LTC4 synthase mRNA in normal neutrophils. However normal neutrophils lack, in contrast to CML neutrophils, LTC4 synthase mRNA in the cytoplasm. This discrepancy is not caused by a stabilized LTC4 synthase RNA in the cytosol of CML neutrophils. Instead an abnormal degradation of LTC4 synthase RNA was found in the cytosol of CML neutrophils. [source] Disease biology rather than age is the most important determinant of survival of patients , 60 years with acute myeloid leukemia treated with uniform intensive therapyCANCER, Issue 10 2005Vikas Gupta M.D. Abstract BACKGROUND The objectives of the current study were to evaluate the outcome of patients , 60 years with acute myeloid leukemia (AML) treated uniformly with high-dose daunorubicin containing induction and modified high-dose cytosine arabinoside containing postremission therapy, and to identify factors predictive of complete disease remission (CR) and survival. METHODS Between 1998 and 2002, the authors treated 117 newly diagnosed patients (acute promyelocytic leukemia excluded) with AML , 60 years (median, 67 years; range, 60,82 years). Karyotype (Medical Research Council classification) at diagnosis was categorized as good risk (n = 3), intermediate risk (n = 69), adverse risk (n = 26), and suboptimal/not done (n = 19). A normal karyotype was seen in 41 patients and 40 (34%) had secondary AML. RESULTS The outcome of induction included the following: CR, 62 (53%); early death, 5 (4%); death during hypoplasia, 14 (12%); and resistant disease, 36 (31%). The 3-year event-free (EFS) and overall survival (OS) rates were 9% (95% confidence interval [95% CI], 3,16%) and 17% (95% CI, 9,29%), respectively. In a univariate analysis, cytogenetics, lactate dehydrogenase level, leukocyte count, and performance status were the significant factors for EFS and OS. Age was not a significant prognostic factor for either CR or survival. In a multivariate model, adverse-risk cytogenetics, previous history of myelodysplastic syndrome or antecedent hematologic disorder, and high leukocyte count (> 30 × 109/L) were independent adverse prognostic factors for survival. The impact of adverse karyotype on EFS and OS was time dependent and was observed after 50 and 150 days, respectively. CONCLUSIONS The authors concluded that candidacy for intensive therapy in older patients should be based on biologic features of disease and fitness, rather than on age. Cancer 2005. © 2005 American Cancer Society. [source] Antimicrobial and Cytotoxic Activities of Neolignans from Magnolia officinalisCHEMISTRY & BIODIVERSITY, Issue 3 2004Wan-Jr Syu In the light of the steady increase of infections related to vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), the medicinal plant Magnolia officinalis was subjected to bioassay-directed fractionation, which led to the isolation of the known neolignans piperitylmagnolol (1), magnolol (2), and honokiol (3) from the MeOH extract. In broth-microdilution assays, 1,3 exhibited antibacterial activities against VRE and MRSA at minimum-inhibitory concentrations (MIC) in the range of 6.25,25,,g/ml, compound 1 being the most-potent antibiotic. The ratio of MBC/MIC (MBC=minimum bactericidal concentration) was ,2 for all compounds. The kinetics of the antibacterial action of 1 and 3 were studied by means of time-kill assays; both compounds were bactericidal against VRE and MRSA, their actions being time dependent, or both time and concentration dependent. Magnolol (2) was acetylated to magnolol monoacetate (4) and magnolol diacetate (5) (partial or full masking of the phenolic OH functions). The cytotoxic properties of 1,5 against human OVCAR-3 (ovarian adenocarcinoma), HepG2 (hepatocellular carcinoma), and HeLa (cervical epitheloid carcinoma) cell lines were evaluated. The CD50 values for compounds 1,3 were in the range of 3.3,13.3,,g/ml, derivatives 4 and 5 being much less potent. This study indicates that piperitylmagnolol (=3-[(1S,6S)-6-isopropyl-3-methylcyclohex-2-enyl]-5,5,-di(prop-2-enyl)[1,1,-biphenyl]-2,2,-diol; 1) possesses both significant anti-VRE activity and moderate cytotoxicity against the above cancer cell lines. [source] | ||||||||||||||||||||||