SEARCH · PubMed Health

Results for “Surrogate variables analysis”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources

PubMed2002

Evaluation of the quantitative insulin sensitivity check index as an estimate of insulin sensitivity in humans.

The goal of this study was to compare estimates of insulin resistance generated by the quantitative insulin sensitivity check index (QUICKI) with a direct measure of insulin-mediated glucose disposal in healthy, nondiabetic volunteers. For this purpose, the results of measurements of plasma glucose and insulin concentrations in 490 nondiabetic, healthy subjects were used to compute several surrogate estimates of insulin resistance, and these values were compared with a direct measure of insulin-mediated glucose disposal. The results of this analysis showed that estimates of insulin resistance derived from use of QUICKI were significantly correlated (r = -.60, P <.001) with direct measures of insulin-mediated glucose in the 490 subjects studied. It was also noted that QUICKI estimates of insulin resistance were highly correlated with fasting insulin concentrations (r = -.98) and the homeostasis model assessment for insulin resistance (HOMA-IR, r = -.99). On the other hand, the correlation between all 3 of the surrogate methods for estimating insulin resistance and the direct assessment of insulin-mediated glucose disposal was relatively weak, i.e., r =.61, r =.64, and r = -.60) for fasting insulin concentration, HOMA-IR, and QUICKI, respectively. The results of these comparisons do not provide support for the superiority of QUICKI over other commonly used surrogate measures of insulin resistance based upon use of fasting insulin concentration or equations utilizing fasting insulin and glucose concentration. Furthermore, none of the 3 surrogate estimates can account for more than approximately 40% of the variability of the difference in insulin-mediated glucose disposal measured directly in 490 healthy, nondiabetic volunteers.

Homeostasis↗

PubMed2003

Linking field-based ecological data with remotely sensed data using a geographic information system in two malaria endemic urban areas of Kenya.

BACKGROUND: Remote sensing technology provides detailed spectral and thermal images of the earth's surface from which surrogate ecological indicators of complex processes can be measured. METHODS: Remote sensing data were overlaid onto georeferenced entomological and human ecological data randomly sampled during April and May 2001 in the cities of Kisumu (population asymptotically equal to 320,000) and Malindi (population asymptotically equal to 81,000), Kenya. Grid cells of 270 meters x 270 meters were used to generate spatial sampling units for each city for the collection of entomological and human ecological field-based data. Multispectral Thermal Imager (MTI) satellite data in the visible spectrum at five meter resolution were acquired for Kisumu and Malindi during February and March 2001, respectively. The MTI data were fit and aggregated to the 270 meter x 270 meter grid cells used in field-based sampling using a geographic information system. The normalized difference vegetation index (NDVI) was calculated and scaled from MTI data for selected grid cells. Regression analysis was used to assess associations between NDVI values and entomological and human ecological variables at the grid cell level. RESULTS: Multivariate linear regression showed that as household density increased, mean grid cell NDVI decreased (global F-test = 9.81, df 3,72, P-value = <0.01; adjusted R2 = 0.26). Given household density, the number of potential anopheline larval habitats per grid cell also increased with increasing values of mean grid cell NDVI (global F-test = 14.29, df 3,36, P-value = <0.01; adjusted R2 = 0.51). CONCLUSIONS: NDVI values obtained from MTI data were successfully overlaid onto georeferenced entomological and human ecological data spatially sampled at a scale of 270 meters x 270 meters. Results demonstrate that NDVI at such a scale was sufficient to describe variations in entomological and human ecological parameters across both cities.

Journal Article↗

PubMed2003

Regression to the mean. A threat to exercise science?

Regression to the mean (RTM) can bias any investigation where the response to treatment is classified relative to initial values for a given variable without the use of an appropriate control group. The phenomenon and resulting errors of interpretation have been recognised by clinicians in a number of disciplines. The causes of RTM include both intra-individual variance and measurement error. The magnitude of RTM can be estimated quite simply, given a knowledge of intra- and inter-individual variance. RTM can be avoided by using a fully controlled experimental design. Difficulties can also be minimised by making duplicate measurements prior to the experimental manipulation, the first measurement serving for classification, and the second (with randomly distributed variance) allowing an assessment of the response to treatment. Less satisfactorily, surrogate measurements (for example, plasma volume for maximal oxygen intake [VO2(max)]) can assess the bias introduced by an initial non-random sorting of study participants. The impact of RTM on the design and interpretation of investigations has as yet received little consideration by exercise scientists and sports physicians. The response to training is often related to initial measurements of a dependent variable such as heart size, ST segmental depression, fitness or level of physical activity. In particular, analyses of this type have been adduced to support the belief that the response to aerobic training is inversely related to an individual's VO2(max). In fact, RTM may account for a major part of this apparent relationship.

Exercise Therapy↗

PubMed1987

Estimation of long term exposure to mixed solvents from questionnaire data: a tool for epidemiological investigations.

Quantifying the exposure of construction painters to mixed organic solvents is difficult in the face of a lack of industrial hygiene data, the heterogeneity of the solvents used, and the variability in work practices which influences the amount of solvents to which a worker is actually exposed. This report describes an attempt to derive an estimate of airborne solvent exposure using questionnaire responses in a population of construction and maintenance painters. This exposure index (EI) is a weighted average of the total number of gallons used a year minus the fraction which would be absorbed by a respirator, where the weights are based on the method of application (spraying, rolling, brushing) and the presence of ventilation (per cent time inside v outside). An analysis performed to determine the sensitivity of the EI to variations in the values chosen for several parameters showed that the index is relatively insensitive to the underlying assumptions that we have used. One component of the EI (self report of hours worked) correlated well with union payroll records. The EI appears to provide a useful relative (not absolute) estimate of airborne exposure to organic solvent mixtures which may be used as a dose surrogate in epidemiological investigations.

Adult↗

PubMed2004

Application of the narcosis target lipid model to algal toxicity and deriving predicted-no-effect concentrations.

The narcosis target lipid model (TLM) was developed to predict the toxicity of chemicals to aquatic organisms that act via narcosis. It is based on the hypothesis that target lipid is the site of toxic action within the organism, that octanol is the appropriate surrogate, and that target lipid has the same physical-chemical properties in all organisms. Here the TLM is extended to available freshwater green algal toxicity data to support a narcosis toxic mode-of-action (TMoA) effect assessment. For each species, significant linear relationships were observed between log(median effective concentration [EC50]) and log(Kow) of the test chemicals. The slope of the log-log relationship statistically was similar to the universal narcosis slope of -0.945 that was derived from an earlier analysis of the TLM to nonalgal species. Critical target lipid body burdens (CTLBB), C(L)* were estimated for each algal species from the intercepts of the regressions and found to be within the range (43-398 micromol/g octanol) reported previously, indicating that algae exhibit a similar sensitivity distribution relative to other aquatic species. The TLM is used to derive the predicted-no-effect concentrations (PNECs) using the hazardous concentration to 5% species (HC5) statistical extrapolation procedure. This calculation requires an analysis of the variability of the universal slope, the C(L)*, and the acute-to-chronic ratio. The PNECs derived using this procedure were consistent with chronic-no-effect concentrations reported for narcotic chemicals. This is in contrast to PNECs derived from limited chemical-specific toxicity data and default application factors. It is concluded that coupling the TLM to the HC5 extrapolation procedure allows optimal use of available toxicity data for deriving environmental quality criteria with a narcotic TMoA.

Animals↗

PubMed1996

Relation between tumor size, quality of life, and survival in patients with colorectal liver metastases.

PURPOSE AND METHODS: This study assessed the relationship between survival, tumor size, and quality of life (QoL; Rotterdam Symptom Checklist [RSC], Hospital Anxiety and Depression Scale [HAD], and Sickness Impact Profile [SIP]) in 50 patients with colorectal liver metastases (CLM). RESULTS: Physical symptom score (RSC) was a stronger survival predictor than tumor size measured on computed tomographic (CT) scan. The best model for predicting survival included QoL questions about diarrhea, eating, restlessness, and ability to work and sleep. The only clinically measured variable included in this best survival prediction model was serum alkaline phosphatase level. This is the first study to show that QoL indices predict survival in CLM. The findings suggest that differences in tumor products and not just in tumor size could influence patient fitness and survival in CLM. Such differences are more accurately estimated by QoL assessment than measurement of tumor size. CONCLUSION: QoL provides a better survival estimate than measurement of tumor size and could be used as a surrogate end point for survival in treatment trials.

Aged↗

PubMed2001

Investigation of an interaction of alcohol intake and family history on breast cancer risk in the Minnesota Breast Cancer Family Study.

BACKGROUND: One explanation for the variability in results in studies of alcohol consumption and breast cancer could be the presence of effect modifiers, such as genetic susceptibility. The authors examined the interaction of alcohol and family history of breast cancer on breast cancer risk in a population-based family study of 426 multigenerational breast cancer families. The authors evaluated whether alcohol use was a stronger risk factor for breast cancer among sisters, daughters, nieces, and granddaughters of breast cancer probands than among women who married into these families. METHODS: Analyses were performed on surrogate and self-reported data combined and on self-reported data alone. To evaluate the interaction of alcohol and breast cancer risk among women with a family history of breast cancer, the authors performed analyses on all 426 families and on a subset of 132 families that had 3 or more breast and/or ovarian cancers in their family. RESULTS: A total of 9032 blood relatives and marry-ins and 558 breast cancer cases were available for analysis. In the entire 426 families, there was a suggestion of an interaction of relationship to the proband and frequency of alcohol consumption on breast cancer risk (P(interaction) = 0.14) for surrogate and self-reported information combined. Among first-degree relatives of the proband, daily drinkers had a significantly increased risk of breast cancer compared with never drinkers (RR = 2.45 [1.20, 5.02]), but this increase was less evident among second-degree relatives who reported daily alcohol intake (RR = 1.27 [0.73, 2.22]) and was not evident in marry-ins who reported daily use of alcohol (RR = 0.90 [0.42, 1.90]). The findings based on the subset of 132 high-risk families with 3 or more breast and/or ovarian cancers were similar to findings based on all 426 families (P(interaction) = 0.07). An interaction of family history with alcohol use was also suggested when the analyses were restricted to self-respondents, although the interaction test P-value was no longer of borderline significance. CONCLUSION: An increased risk of breast cancer due to an increased frequency of alcohol consumption may be limited to women with a family history of breast cancer.

Adult↗

PubMed2006

Adiponectin and its correlates of cardiovascular risk in young adults: the Bogalusa Heart Study.

Adiponectin, a novel adipocytokine produced exclusively in the adipose tissue, plays a major role in the development of metabolic syndrome, type 2 diabetes mellitus, and related cardiovascular (CV) diseases. However, information is scant regarding the association of adiponectin with measures of CV risk in young adults. This aspect was examined in a biracial (black-white) community-based sample of 1153 individuals (mean age, 36.2 years; 70% white, 43% male) who participated in the Bogalusa Heart Study. Adiponectin levels showed race (white > black, P < .0001) and sex (female > male, P < .0001) differences, and correlated significantly in a beneficial manner to measures of obesity (body mass index, waist circumference, and abdominal height), mean arterial blood pressure, lipoprotein variables (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), measures of glucose homeostasis (insulin, glucose, homeostasis model assessment of insulin resistance [HOMA-IR]), and uric acid, after adjusting for age, race, sex, and cigarette smoking. In multivariate analysis that used either body mass index or abdominal height as a measure of general and visceral adiposity in 2 separate models, HOMA-IR was the major contributor explaining 18.4% and 18.1% of the variance, respectively. There was a significant interaction between abdominal height and HOMA-IR on adiponectin level in that the inverse association between adiponectin and insulin resistance was pronounced at higher level of visceral adiposity. Furthermore, adiponectin levels decreased with increasing number of metabolic syndrome risk factors defined by the National Cholesterol Education Program Adult Treatment Panel III (P for trend <.0001). Moreover, adiponectin levels were low among those with positive parental histories of coronary heart disease (P = .03), hypertension (P = .04), and type 2 diabetes mellitus (P = .01), considered as surrogate measures of risk. These findings, by showing an inverse association of adiponectin with insulin resistance, visceral adiposity, and related metabolic syndrome, and also with positive parental histories of coronary heart disease, hypertension, and type 2 diabetes mellitus, underscore the value of adiponectin in CV and type 2 diabetes mellitus risk assessments in young adults.

Adiponectin↗

PubMed2001

Predictors of response to strontium-89 (Metastron) in skeletal metastases from prostate cancer: report of a single centre's 10-year experience.

An analysis of prospectively collected data from 75 patients with bone metastases secondary to prostate cancer who were treated with strontium-89 injection in a single centre over a 10-year period, is presented. The surrogate role of markers of disease progression (haemoglobin and prostate specific (PSA) antigen levels; number of bone scan-positive sites), symptomatic factors (analgesic intake; number of painful bone sites) and history of prior external radiotherapy, were analysed to determine whether any parameters had a predictive effect on the success of strontium-89 treatment. The success of strontium-89 injection was determined by calculating the change in number of sites of bone pain (pain sites) and analgesic intake. The outcome was classed as successful in 42 (56.0%) patients, unsuccessful in 13 (17.3%) and unchanged in 20 (26.7%). Proportionately more of the patients who had 'superscans' on bone scintigraphy at baseline had an unsuccessful outcome after a strontium-89 injection (5/7; 71.4%); for those with fewer bone scan-positive sites the majority had successful outcomes. Patients with a successful outcome had a significantly better survival rate after strontium-89 injection. Multivariate analysis showed haemoglobin level, PSA level and outcome after strontium-89 treatment to be significant independent prognostic variables; no change/unsuccessful outcome, a high PSA level prior to treatment, and a low haemoglobin level were associated with poor survival. It is suggested that early treatment with strontium-89 (Metastron) in patients with fewer bone metastases is more likely to be successful, with a longer time before further therapy required.

Aged↗

PubMedDate not supplied

An analysis of blood lead data in clinical records by external data on lead pipes and age of household.

This study examined the possibility that lead pipes in the drinking water distribution system were elevating the blood lead levels of children in London, Ontario, Canada. Based on their postal codes, 164 children admitted between 1984 and 1989 to an institution for the behaviorally disordered or developmentally challenged were categorized according to whether they lived in the area of the city known by the local Public Utilities Commission to be serviced by lead pipes. Analysis of covariance was used to obtain confounder-adjusted geometric means in each area. After adjusting for gender, year of lead test (a surrogate for gasoline source), and census tract prevalence of low family income, children in the lead service area (LSA) were found not to have higher blood lead levels (geometric means: LSA = 4.7 micrograms/dl, Non-LSA = 4.8 micrograms/dL; p = 0.839). The average blood lead level declined 60.9% between 1984 and 1989. Using municipal tax assessment data on the age of each child's home, those children living in homes built during or before 1945 (when interior paints were as much as 50% lead by dry weight) had an average blood lead level that was 62.3% higher (p = 0.011) than that of those in homes built since 1975 (when interior paints were limited to no higher than 0.5% lead by dry weight). A clear gradient was observed. This association with age of home remained significant after adjusting for gender, diagnosis, and year of lead test. Variables indicating the amount of industry near the child's residence and the presence of lead service pipes did not enter the model after house-age. In conclusion, no evidence indicated that the lead service pipes were elevating blood lead levels in these London children. The data suggest that with the removal of lead from gasoline, lead-based paint is a significant remaining source of lead exposure. Little data are available on childhood lead exposure from paint in Canada. The present descriptive data suggest that more research into this potential problem in Canada is warranted.

Adolescent↗

PubMed2001

Toxicity of mono-, di- and tri-chlorophenols to lux marked terrestrial bacteria, Burkholderia species Rasc c2 and Pseudomonas fluorescens.

Burkholderia species RASC and Pseudomonas fluorescens were marked with lux genes, encoding for bioluminescence and used to assess the toxicity of mono-, di- and tri-chlorophenols by determining the decline in bioluminescence following exposure to the compounds in aqueous solution. Toxicity was expressed as a 50% effective concentration value (EC50, equating to the concentration of compound which caused a 50% decline in bioluminescence. Comparing the toxicity values of the compounds showed that, in general, increasing the degree of chlorination, increased toxicity. By carrying out forward multiple linear regressions with log10 EC50 values and physio-chemical descriptors, it was shown that molecular parameters describing the hydrogen bonding nature of a chlorophenol provided a better fit than regressions between toxicity data and log10 Kow alone. Utilising these descriptor variables in equations, it was shown that the toxicity of chlorophenols to the lux marked bacteria could be predicted from the compounds physio-chemical characteristics. By correlating lux marked RASC c2 and P. fluorescens EC50 values with toxicity values using Pimephales promelas (fathead minnow), Tetrahymena pyriformis (ciliate) and marine bacterium Vibriofischeri, it was apparent that lux marked RASC c2 correlated well with the freshwater aquatic species (P. promelas and T. pyriformis). This implied that for predictions of toxicity of organic xenobiotic compounds to higher organisms, lux marked RASC c2 could be utilised as a rapid surrogate.

Bacterial Proteins↗

PubMed2001

Prognostic significance of circulating microsatellite markers in the plasma of melanoma patients.

PURPOSE: Multiple genetic alterations including loss of heterozygosity (LOH) occur commonly in melanoma tumors. We demonstrated previously free-circulating DNA microsatellites with LOH in the blood of melanoma patients. These LOH markers in plasma may be useful as surrogates for subclinical disease progression. The purpose of this study was to determine whether the presence of circulating tumor microsatellite markers in the preoperative blood from patients with melanoma has prognostic utility. EXPERIMENTAL DESIGN: Plasma was analyzed for the presence of LOH at six chromosome regions, which are common for allelic loss in melanoma tumors, in 57 patients undergoing surgical resection of all of the clinically apparent disease. RESULTS: LOH was detected in 32 of 57 patients (56%). Both LOH incidence and frequency correlated with advancing American Joint Committee on Cancer stage. In patients with American Joint Committee on Cancer stage III, the presence of LOH as an independent variable in preoperative plasma was significantly associated (P = 0.05) with an increased risk of death. Furthermore, LOH at microsatellite marker D1S228 in the plasma of patients with advanced disease correlated significantly (P = 0.0009) with a poorer survival after surgical resection. LOH commonly found in melanoma tumors can be successfully identified in the plasma of a patient, providing a potentially less invasive route for following genetic changes that serve as molecular surrogates for assessing subclinical disease progression. CONCLUSIONS: This study provides evidence that blood testing for circulating tumor genetic markers may provide valuable prognostic information and guide future therapy.

DNA, Neoplasm↗

PubMed2006

Linear regression model for predicting patient-specific total skeletal spongiosa volume for use in molecular radiotherapy dosimetry.

UNLABELLED: The toxicity of red bone marrow is widely considered to be a key factor in restricting the activity administered in molecular radiotherapy to suboptimal levels. The assessment of marrow toxicity requires an assessment of the dose absorbed by red bone marrow which, in many cases, requires knowledge of the total red bone marrow mass in a given patient. Previous studies demonstrated, however, that a close surrogate-spongiosa volume (combined tissues of trabecular bone and marrow)-can be used to accurately scale reference patient red marrow dose estimates and that these dose estimates are predictive of marrow toxicity. Consequently, a predictive model of the total skeletal spongiosa volume (TSSV) would be a clinically useful tool for improving patient specificity in skeletal dosimetry. METHODS: In this study, 10 male and 10 female cadavers were subjected to whole-body CT scans. Manual image segmentation was used to estimate the TSSV in all 13 active marrow-containing skeletal sites within the adult skeleton. The age, total body height, and 14 CT-based skeletal measurements were obtained for each cadaver. Multiple regression was used with the dependent variables to develop a model to predict the TSSV. RESULTS: Os coxae height and width were the 2 skeletal measurements that proved to be the most important parameters for prediction of the TSSV. The multiple R(2) value for the statistical model with these 2 parameters was 0.87. The analysis revealed that these 2 parameters predicted the estimated the TSSV to within approximately +/-10% for 15 of the 20 cadavers and to within approximately +/-20% for all 20 cadavers in this study. CONCLUSION: Although the utility of spongiosa volume in estimating patient-specific active marrow mass has been shown, estimation of the TSSV in active marrow-containing skeletal sites via patient-specific image segmentation is not a simple endeavor. However, the alternate approach demonstrated in this study is fairly simple to implement in a clinical setting, as the 2 input measurements (os coxae height and width) can be made with either pelvic CT scanning or skeletal radiography.

Bone Marrow↗

PubMed2004

Measurement of structural progression in osteoarthritis of the hip: the Barcelona consensus group.

OBJECTIVE: To outline the best available method of measurement for detecting progression of osteoarthritis (OA) of the hip especially in therapeutic trials. METHOD: A Medline search of articles related to progression of hip OA was performed. A group of experts met over a 1.5-day session to review available literature and new research. Specific questions were addressed in order to reach a consensus on measuring progression of OA of the hip. RESULTS: Of the available surrogate measures, a single yearly standing or reclined antero-posterior plain radiograph of the pelvis with feet internally rotated 15-20 degrees, can be evaluated with the use of an atlas for joint space width (JSW, interbone distance). There should be a minimum JSW upon baseline screening that may be 1 or 2 mm. Digitization of films offers a slight reduction in variability of measurements. Progression of OA can be calculated by measurement of the JSW on paired and blinded films. A reduction of > or = 0.5 mm is greater than the 'minimum perceptible difference' as well as the variation of most imaging techniques, and represents a clinically relevant and significant reduction in the JSW. Narrowing of the superomedial or superolateral JSW may tend to progress more rapidly than other changes. In clinical trials, patients who discontinue the study treatment need to be followed after discontinuation, and an imputation strategy which provides unbiased estimates of both the treatment effect and its variance is an appropriate technique for intent-to-treat analysis. CONCLUSION: For the development of new agents intended to prevent, retard, stabilize or reverse the progress of OA of the hip, the radiographic methodology presently available is adequate to detect changes in hip JSW of OA.

Arthroscopy↗

PubMed1994

Mimicry of a neutralizing epitope of the major outer membrane protein of Chlamydia trachomatis by anti-idiotypic antibodies.

The major outer membrane protein (MOMP) is a primary target antigen for the development of chlamydial vaccine. This protein is composed of four variable domains (I to IV) flanked by constant regions. Some of the variable domains contain antigenic determinants that elicit a neutralizing antibody response. Murine monoclonal antibodies (MAbs) against three nonoverlapping epitopes of MOMP were developed. One of these, called DP10, bound to all serovars, as shown by immunoblot analysis, and neutralized chlamydial infectivity for hamster kidney (HaK) cells in a complement-independent in vitro assay. Furthermore, analysis of the fine specificity of this MAb showed that it recognized a synthetic peptide contained within variable domain IV of the MOMP. Anti-idiotypic antibodies (aId) directed against this anti-MOMP MAb were produced in rabbits. These aId specifically bound to the relevant idiotype (DP10) and inhibited the binding of anti-MOMP MAb (DP10) to MOMP preparations in a dose-dependent fashion. The specificity of our aId for the binding site of anti-MOMP MAb is further suggested by the binding inhibition of affinity-purified aId to DP10 by the synthetic peptide defined by the idiotype. In addition, these aId also reacted with anti-MOMP antisera from rats and mice, suggesting an idiotypic cross-reactivity between these species. Finally, immunization of naive mice with aId induced an antibody response directed against the peptide defined by our anti-MOMP MAb and with neutralizing activity. Taken together, these data suggest that aId mimic a neutralization site on MOMP and could serve as a surrogate antigen to induce protective immunity against Chlamydia trachomatis.

Amino Acid Sequence↗

PubMed2001

Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833.

PURPOSE: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion. PATIENTS AND METHODS: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833. RESULTS: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C(pss)) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma. CONCLUSION: PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

ZAP-70 expression in B-cell chronic lymphocytic leukemia: evaluation by external (isotypic) or internal (T/NK cells) controls and correlation with IgV(H) mutations.

BACKGROUND: Expression of T cell specific zeta-associated protein 70 (ZAP-70) by B-cell chronic lymphocytic leukemia (B-CLL) cells, as investigated by flow cytometry, has both prognostic relevance and predictive power as surrogate for immunoglobulin heavy chain variable region (IgV(H)) mutations, although a standardization of the cytometric protocol is still lacking. METHODS: Flow cytometric analyses for ZAP-70 were performed in peripheral blood samples from 145 B-CLL (124 with IgV(H) mutations) by a standard three-color protocol. Identification of ZAP-70(+) cell population was based on an external negative control, i.e., the isotypic control (ISO method) or an internal positive control, i.e., the population of residual normal T/NK cells (TNK method). A comparison between these two approaches was performed. RESULTS: While 86/145 cases were concordant as for ZAP-70 expression according to the two methods (ISO(+)TNK(+) or ISO(-)TNK(-)), 59/145 cases had discordant ZAP-70 expression, mainly (56/59) showing a ISO(+)TNK(-) profile. These latter cases express higher levels of ZAP-70 in their normal T cell component. Moreover, discordant ISO(+)TNK(-) cases had a IgV(H) gene mutation profile similar to that of concordantly positive cases and different from ZAP-70 concordantly negative B-CLL. CONCLUSION: Analysis of ZAP-70 expression by B-CLL cells by using the ISO method allows to overcome the variability in the expression of ZAP-70 by residual T cells and yields a better correlation with IgV(H) gene mutations. A receiver operating characteristic analysis suggests to employ a higher cut-off than the commonly used 20%. A parallel evaluation of the prognostic value of ZAP-70 expression, as determined according to the ISO and TNK methods, is still needed.

Adult↗

PubMed2005

Evaluation of facial features on particle inhalation.

Computational fluid dynamics (CFD) and numerical investigations of particle inhalability and contaminant exposure have used simple geometrical surrogates for a breathing human form, but the effect of eliminating facial features has not been investigated. In this work, the velocity field and particle aspiration associated with two differently shaped mannequins were investigated to determine if an elliptical form was sufficient to represent the complexity of fluid flow associated with an inhaling human. Laser Doppler anemometry was used to measure velocity, and both optical sizing and gravimetric analysis were used to measure particle aspiration from an aerosol source. All tests were performed with continuous inhalation through the mouth, with the mannequin facing the 0.3 m s(-1) freestream. Although limitations in the laser Doppler optics prevented velocity measurements at distances <11 mm in front of the mannequin mouth opening, significant velocity differences were identified up to 20 mm in front of the mouth opening. This indicated that facial features affected the flow field near the face only. Owing to these differences, particle aspiration was compared between mannequins for three different velocity ratio conditions using an aerosol source. Even with relatively large variability in the aspirated concentration in this study, the aspirated mass concentration was significantly less for the anatomical mannequin relative to the elliptical form. Thus, the simplified elliptical cylinder does not sufficiently characterize the fluid dynamics near the mouth of an inhaling human form at these limited test conditions. Future CFD and numerical simulations to investigate human aspiration of particles should incorporate the complex features of the human face to investigate adequately particle aspiration in low velocity environments.

Air Movements↗