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D L Davis

Publications and source records attributed to D L Davis.

At least 37 records · Page 2Linked to original sources
PubMed2000

Minor immunophilin binding of tacrolimus and sirolimus metabolites.

OBJECTIVES: We have previously identified three minor immunophilins of molecular weights 37 kDa, 14 kDa, and 5-8 kDa capable of binding tacrolimus and sirolimus. DESIGN AND METHODS: When tested against pure preparations of five sirolimus metabolites, the 14 kDa protein had almost no cross-reactivity, the 37 kDa protein cross-reacted from a high of 23.2% to <10% and the 5-8 kDa protein cross-reacted from <10% to 46.4%. When the 5-8 kDa immunophilin was tested in whole blood samples to assess interference in clinical samples, the demethylated sirolimus metabolites showed about 25% less cross-reactivity while the hydroxylated metabolites reacted about the same. RESULTS: Since MLC data on sirolimus metabolites to date indicates that their pharmacologic potencies are < or =10% of the parent, the 14 kDa immunophilin appears to be the best candidate for a sirolimus radioreceptor assay. The 5-8 kDa immunophilin is newly identified and its cross-reactivity with tacrolimus metabolites had not been assessed. Binding of the 5-8 kDa immunophilin to pure preparations of three tacrolimus metabolites showed virtually no binding of the protein to 13-O-demethyl and 31-O-demethyl tacrolimus and binding to 15-O-demethyl tacrolimus at 121% relative to parent tacrolimus. Cross-reactivity of 15-O-demethyl tacrolimus with the 5-8 kDa protein was then assessed in whole blood samples, and it bound at a level of 163%. MLC data indicates that 31-O-demethyl tacrolimus is equipotent to parent tacrolimus in immunosuppressive activity, while the 13-O-demethyl and 15-O-demethyl have negligible immunosuppressive activity. CONCLUSIONS: Therefore, the 5-8 kDa immunophilin would have limitations in a radioreceptor assay for tacrolimus. In addition, we have evidence that the 5-8 kDa immunophilin is a subunit of a 52 kDa immunophilin previously identified by our group, and the cross-reactivity of the 5-8 kDa immunophilin with these metabolites is similar to that found previously with the 52 kDa, indicating that the two proteins could be related.

Animals↗
PubMed2000

Comparison of steady-state trough sirolimus samples by HPLC and a radioreceptor assay.

OBJECTIVES: We have previously identified a minor immunophilin of 52 kDa molecular weight capable of binding tacrolimus and sirolimus. Because immunophilins are capable of binding both parent drug and metabolites and HPLC assays are typically used to assess parent drug in clinical situations, we used this immunophilin in a radioreceptor assay (RRA) to determine if any metabolites not included in the HPLC measurement would bind to the immunophilin and be associated with thrombocytopenia in patients receiving sirolimus. DESIGN AND METHODS: We tested 51 steady-state trough whole blood samples from non-thrombocytopenic patients and 51 steady-state trough samples from thrombocytopenic patients and compared them to HPLC measurements of parent drug in the same samples. We also tested whole blood samples spiked with authentic sirolimus metabolites using RRA to ascertain the effect these metabolites have on the technique. RESULTS: We found minimal cross-reactivity in this assay for sirolimus metabolites (binding ranged from <10% to 26%), and good correlation of the radioreceptor assay with HPLC (linear regression slope 0.92, y-intercept 0.79). There was no statistically significant difference between the RRA and HPLC results in two patient groups-thrombocytopenic and non-thrombocytopenic-using the paired t-test (p<0.005) and Bland-Altman analysis. CONCLUSIONS: These findings indicate that although the RRA could be substituted for HPLC in therapeutic drug monitoring, the 52 kDa immunophilin does not offer an advantage in terms of detecting metabolites associated with thrombocytopenia. However, the RRA offers the advantages of shorter turnaround time, smaller sample volume and potential for automation.

Animals↗
PubMed2000

Biochemical characterization of the minor immunophilins.

OBJECTIVE: We present biochemical characterization of the previously described 14 kDa, 37 kDa, and 52 kDa immunophilins and a newly identified 5-8 kDa immunophilin. DESIGN AND METHODS: Proteins were tested for the following enzymatic activities-rotamase, G3PDH, protein kinase C, cAMP dependent protein kinase-and for the ability to inhibit calcineurin phosphatase when complexed with tacrolimus (FK506). RESULTS: The 5-8 kDa protein, like the other minor immunophilins, lacks rotamase activity. Since the 37 kDa possesses G3PDH activity, the 5-8 kDa protein, 14 kDa protein, and 52 kDa protein were all tested and found to lack G3PDH activity. Additional work shows that none of the minor immunophilins possess protein kinase C or cyclic AMP-dependent protein kinase activity and that the 37 kDa and 5-8 kDa and probably the 52 kDa proteins are capable of inhibiting calcineurin phosphatase when bound to tacrolimus.

Amino Acid Sequence↗
PubMed2000

A comparison of sexually abused and non-sexually abused adolescents in a clinical treatment facility using the MMPI-A.

OBJECTIVE: In the current study, the adolescent version of the Minnesota Multiphasic Personality Inventory, the MMPI-A, was used to address concerns voiced about the mixing of different developmental ages, use of inadequate comparison groups, and the lack of reliance on reliable and valid measures of psychological, behavioral, and psychosocial problems used in previous studies of sexually abused children and adolescents. METHOD: A total of 107 adolescents in residential treatment (73 boys and 34 girls) were included in the study. Seventy-two of these adolescents had reportedly been sexually abused (42 boys and 30 girls); 35 had not been abused (31 boys and 4 girls). Predictions based on previous research with adolescents were made and tested regarding which MMPI-A validity, clinical, and content scales would differ between the sexually abused and non sexually abused groups of adolescents. RESULTS: Overall, and consistent with many predictions, sexually abused adolescents had both statistically and clinically higher elevations on several MMPI-A scales than did their non-abused counterparts. No scales were more elevated for non-abused adolescents than for abused adolescents. CONCLUSIONS: Sexually abused adolescents in residential treatment, as a group, present with concerns that their non-abused counterparts did not have, or did not share to the same extent. Treatment recommendations based on the MMPI-A scale elevations are provided, limitations of the current study discussed, and directions for further research are suggested.

Adolescent↗
PubMed2000

An immunophilin-binding assay for sirolimus.

OBJECTIVE: This review examines the performance of 4 assays for sirolimus in terms of their ability to meet 6 guidelines determined by a panel of experts. BACKGROUND: Four methods have been described to date for the analysis of sirolimus concentrations in whole blood: high-performance liquid chromatography-mass spectrometry (HPLC-MS); microparticle enzyme immunoassay (MEIA); p70 S6 kinase inhibition; and an immunophilin-binding assay (IBA). METHODS: A MEDLINE search of the literature was performed to identify relevant studies. RESULTS: The HPLC methods suffer from precision problems because of the substantial specimen preparation required, and HPLC-MS methods are not practical for clinical use. Initial studies of the MEIA have found overestimation of sirolimus concentrations that may be caused by antibody cross-reactivity with sirolimus metabolites. Monitoring of sirolimus effects by p70 S6 kinase inhibition is as yet possible only theoretically, and the assay itself is not yet optimal. With the IBA, use of a T-cell protein that binds to sirolimus and that may be the intracellular target of the drug as the assay binding protein allows the assay to measure sirolimus selectively, even in the presence of structurally similar metabolites. CONCLUSION: More than 200 clinical samples have been analyzed by the IBA, and correlation with HPLC values has been good, with a regression line slope near 1.0. In addition, the assay is easier to perform and more precise than HPLC, and has the potential to be automated. Thus, the IBA appears to have certain clear advantages over the other assays.

Chromatography, High Pressure Liquid↗
PubMed2000

The bile acid synthetic gene 3beta-hydroxy-Delta(5)-C(27)-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis.

We used expression cloning to isolate cDNAs encoding a microsomal 3beta-hydroxy-Delta(5)-C(27)-steroid oxidoreductase (C(27) 3beta-HSD) that is expressed predominantly in the liver. The predicted product shares 34% sequence identity with the C(19) and C(21) 3beta-HSD enzymes, which participate in steroid hormone metabolism. When transfected into cultured cells, the cloned C(27) 3beta-HSD cDNA encodes an enzyme that is active against four 7alpha-hydroxylated sterols, indicating that a single C(27) 3beta-HSD enzyme can participate in all known pathways of bile acid synthesis. The expressed enzyme did not metabolize several different C(19/21) steroids as substrates. The levels of hepatic C(27) 3beta-HSD mRNA in the mouse are not sexually dimorphic and do not change in response to dietary cholesterol or to changes in bile acid pool size. The corresponding human gene on chromosome 16p11.2-12 contains six exons and spans 3 kb of DNA, and we identified a 2-bp deletion in the C27 3beta-HSD gene of a patient with neonatal progressive intrahepatic cholestasis. This mutation eliminates the activity of the enzyme in transfected cells. These findings establish the central role of C(27) 3beta-HSD in the biosynthesis of bile acids and provide molecular tools for the diagnosis of a third type of neonatal progressive intrahepatic cholestasis associated with impaired bile acid synthesis.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

Utility of a brief self-efficacy scale in clinical training program evaluation.

Self-efficacy is often studied as a predictor of professional practice behaviors or as an outcome of clinical training, using brief scales with little validation. This study examines the utility of a brief self-efficacy scale in the evaluation of a clinical training program. Subjects were 119 registered dietitians who participated in diabetes training. Hypothesized relationships between self-efficacy ratings and indices of skill mastery, participation in training, and subsequent practice change were examined. Self-efficacy ratings after training correlated significantly with relevant prior experience (r = .4 and .29, p < .01) but not total experience and with knowledge post-test score (r = .21, p < .02). Self-efficacy for all 12 program objectives increased significantly after training. Post-training self-efficacy for two program objectives correlated significantly with self-reported successful practice changes related to those objectives (r = .4, p < .04 and r = .51, p < .01). The data suggest that brief self-efficacy assessments can contribute meaningfully to clinical training program evaluation.

Analysis of Variance↗
PubMed2000

Morphology of luminal and glandular epithelial cells from pig endometrium grown on plastic or extracellular matrices.

Luminal (LE) and glandular epithelial (GE) cells from d-13 pregnant pigs were cultured on plastic, matrix secreted from endometrial stroma, and EHS matrix (Matrigel) in culture medium (RPMI-1640) supplemented with 20 and 10% fetal bovine serum, respectively. After culture for 7 and 14 d, GE and LE cells were prepared for transmission and GE cells for scanning electron microscopy. The two types of endometrial epithelial cells displayed different morphological characteristics when grown on different culture substrates. On plastic, the GE and LE cells formed flattened monolayers. However, stroma-secreted matrix directed the polarization of endometrial epithelia. The GE and LE cells reacted differently to thick Matrigel coatings; LE cells formed a colony after 7 d of culture and then proliferated further to form a colony with a cavity, but GE cells organized to form a colony with a shallow depression in the center at 7 d and developed duct-like structures after 14 d in vitro. Luminal epithelial cells grown on either diluted or thin-coated Matrigel and grown on stroma-secreted matrix formed a monolayer but no three-dimensional structures.

Animals↗
PubMed1999

Computed radiography dual energy subtraction: performance evaluation when detecting low-contrast lung nodules in an anthropomorphic phantom.

A dedicated chest computed radiography (CR) system has an option of energy subtraction (ES) acquisition. Two imaging plates, rather than one, are separated by a copper filter to give a high-energy and low-energy image. This study compares the diagnostic accuracy of conventional computed radiography to that of ES obtained with two radiographic techniques. One soft tissue only image was obtained at the conventional CR technique (s = 254) and the second was obtained at twice the radiation exposure (s = 131) to reduce noise. An anthropomorphic phantom with superimposed low-contrast lung nodules was imaged 53 times for each radiographic technique. Fifteen images had no nodules; 38 images had a total of 90 nodules placed on the phantom. Three chest radiologists read the three sets of images in a receiver operating characteristic (ROC) study. Significant differences in Az were only found between (1) the higher exposure energy subtracted images and the conventional dose energy subtracted images (P = .095, 90% confidence), and (2) the conventional CR and the energy subtracted image obtained at the same technique (P = .024, 98% confidence). As a result of this study, energy subtracted images cannot be substituted for conventional CR images when detecting low-contrast nodules, even when twice the exposure is used to obtain them.

Analysis of Variance↗
PubMed1999

Unexplained increases in cancer incidence in the United States from 1975 to 1994: possible sentinel health indicators?

To search for unexplained patterns in cancer incidence, we analyzed data from 1975 to 1994 that represent approximately 10% of the population of the United States. Our analysis focused on long-term time trends in incidence and on deviations from those trends attributable to birth cohorts or to calendar periods. On average, cancer incidence rose 0.8% annually in white women and 1.8% in white men. After removing several cancers related to smoking and increased screening, average annual increases fell to 0.1% in white women but persisted at 1.7% in white men. In particular, yearly increases in non-Hodgkin's lymphoma averaged 2.4% in white women and 4.7% in white men. Among men, incidence changes attributable to cohorts grew progressively larger from one cohort to the next. Cancer incidence patterns among black men and women were similar to those among whites despite smaller population sizes. Unexplained patterns of cancer incidence may signal changes in underlying risk factors and highlight the continuing need for research on cancer etiology and prevention.

Adult↗
PubMed1999

Evaluation of a multicomponent, behaviorally oriented, problem-based "summer school" program for adolescents with diabetes.

A 2-week summer school program, combining problem-based learning with behavior therapy, was developed to help adolescents with insulin-dependent diabetes improve their ability to cope with obstacles to dietary management. Ten students participated in a first session, and 9 participated in a second session, serving as a waiting list control group. Outcomes were evaluated pre- and postsession and at a 4-month follow-up using 3-day food diaries, blood glucose data, and paper-and-pencil tests of diabetes-related knowledge, self-efficacy, coping strategies, and general problem solving. Improvements were observed in self-efficacy, problem-solving skills, and self-reported coping strategies. No significant changes were observed in daily intake of fat, cholesterol, calories, mean blood glucose levels or blood glucose variability, and diabetes knowledge. Comparisons between the first group and the waiting list control group do not allow the significant pre-post changes to be clearly attributed to the summer school program.

Adolescent↗
PubMed1999

Water pollution and human health in China.

China's extraordinary economic growth, industrialization, and urbanization, coupled with inadequate investment in basic water supply and treatment infrastructure, have resulted in widespread water pollution. In China today approximately 700 million people--over half the population--consume drinking water contaminated with levels of animal and human excreta that exceed maximum permissible levels by as much as 86% in rural areas and 28% in urban areas. By the year 2000, the volume of wastewater produced could double from 1990 levels to almost 78 billion tons. These are alarming trends with potentially serious consequences for human health. This paper reviews and analyzes recent Chinese reports on public health and water resources to shed light on what recent trends imply for China's environmental risk transition. This paper has two major conclusions. First, the critical deficits in basic water supply and sewage treatment infrastructure have increased the risk of exposure to infectious and parasitic disease and to a growing volume of industrial chemicals, heavy metals, and algal toxins. Second, the lack of coordination between environmental and public health objectives, a complex and fragmented system to manage water resources, and the general treatment of water as a common property resource mean that the water quality and quantity problems observed as well as the health threats identified are likely to become more acute.

Agriculture↗
PubMed1998

Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.

We describe a metabolic defect in bile acid synthesis involving a deficiency in 7alpha-hydroxylation due to a mutation in the gene for the microsomal oxysterol 7alpha-hydroxylase enzyme, active in the acidic pathway for bile acid synthesis. The defect, identified in a 10-wk-old boy presenting with severe cholestasis, cirrhosis, and liver synthetic failure, was established by fast atom bombardment ionization-mass spectrometry, which revealed elevated urinary bile acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids, and an absence of primary bile acids. Gas chromatography-mass spectrometric analysis confirmed the major products of hepatic synthesis to be 3beta-hydroxy-5-cholenoic and 3beta-hydroxy-5-cholestenoic acids, which accounted for 96% of the total serum bile acids. Levels of 27-hydroxycholesterol were > 4,500 times normal. The biochemical findings were consistent with a deficiency in 7alpha-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7alpha-hydroxylase activity was undetectable in the patient. Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon. The truncated protein was inactive when expressed in 293 cells. These findings indicate the quantitative importance of the acidic pathway in early life in humans and define a further inborn error in bile acid synthesis as a metabolic cause of severe cholestatic liver disease.

Amino Acid Sequence↗
PubMed1998

Reduced ratio of male to female births in several industrial countries: a sentinel health indicator?

CONTEXT: The sex ratio of 1.06:1, the ratio of male to female births, has declined over the past decades. Recent reports from a number of industrialized countries indicate that the proportion of males born has significantly decreased, while some male reproductive tract disorders have increased. OBJECTIVES: To examine the evidence for declines in the male proportion at birth and suspected causes for this decline, and to determine whether altered sex ratio can be considered a sentinel health event. DATA SOURCES: Birth records were analyzed from national statistical agencies. STUDY SELECTION: Published analyses of trends in ratio of males to females at birth and studies of sex determinants evaluating epidemiological and endocrinological factors. DATA EXTRACTION: Proportion of males born: 1950-1994 in Denmark; 1950-1994 in the Netherlands; 1970-1990 in Canada; and 1970-1990 in the United States. DATA SYNTHESIS: Since 1950, significant declines in the proportion of males born have been reported in Denmark and the Netherlands. Similar declines have been reported for Canada and the United States since 1970 and parallel declines also have occurred in Sweden, Germany, Norway, and Finland. In Denmark, the proportion of males declined from 0.515 in 1950 to 0.513 in 1994. In the Netherlands, the proportion of males declined from 0.516 in 1950 to 0.513 in 1994. Similar declines in the proportion of males born in Canada and the United States are equivalent to a shift from male to female births of 8600 and 38000 births, respectively. Known and hypothesized risk factors for reduced sex ratio at birth cannot fully account for recent trends. CONCLUSION: Patterns of reduced sex ratio need to be carefully assessed to determine whether they are occurring more generally, whether temporal or spatial variations are evident, and whether they constitute a sentinel health event.

Canada↗
PubMed1998

Prostate cancer treatment with radioactive seed implantation.

Prostate cancer is the second leading cause of cancer death after lung cancer. The use of radioactive seeds (i.e., brachytherapy) to provide radiation therapy is one of the three recommended treatment options for localized carcinoma of the prostate. This technique places the radioactive source in close proximity to the malignancy and provides a predictable dose of radiation to a confined area, thus sparing nearby healthy tissue. The technique is performed under transrectal ultrasonography. Nursing care for the patient undergoing this ambulatory surgery procedure focuses on detailed preoperative instructions and highly technical intraoperative care, followed by individualized postoperative care.

Brachytherapy↗
PubMed1998

Tacrolimus metabolite cross-reactivity in different tacrolimus assays.

OBJECTIVES: Tacrolimus (FK506) is an immunosuppressive drug with great clinical promise. There is a controversy regarding the role of tacrolimus metabolites in immunosuppression and toxicity, and immunoassays and immunophilin binding assays have not been adequately tested for metabolite cross-reactivity. Methods are limited to HPLC and HPLC-MS for quantifying the parent drug. Mixed lymphocyte culture assay (MLC) is the preferred functional bioassay for the measurement of parent drug and active metabolites but it is not practical for routine laboratory use. Due to differences in assay methods and reagent specificity, the concentration of tacrolimus in a given specimen may vary among different assay kit manufacturers. The objective of this study was to evaluate the degree of cross-reactivity or interference of the three first-generation tacrolimus metabolites [13-O-demethyl (M-I), 31-O-demethyl (M-II) and 15-O-demethyl (M-III)] among two different tacrolimus immunoassays (Immunoassay: PRO-Trac II FK506, Abbott IMx tacrolimus-II); and the radioreceptor assays (RRA) using minor immunophilins (14, 37, and 52 kDa immunophilins) and tacrolimus binding protein (FKBP12). METHODS: First-generation tacrolimus metabolites (M-I, M-II, and M-III) spiked in drug-free whole blood were assayed with RRA using three minor immunophilins (14, 37, and 52 kDa) and two commercial immunoassay procedures (Incstar PRO-Trac II tacrolimus, Abbott IMx tacrolimus II). The results were compared to previously published FKBP-12 RRA data and their immunosuppressive potency. RESULTS AND CONCLUSION: The first generation tacrolimus metabolites (M-I, M-II, and M-III) were tested using concentrations of 10 and 20 ng/mL. The significance of the metabolite interference (% of the total interference) was calculated based on the relative concentration of each metabolite present at steady-state trough concentrations in renal transplant recipients (22). Metabolite I, which has no functional immunosuppressive activity showed minimal interference compared to M-II and M-III in all assays except the 14 kDa RRA. The Incstar PRO-Trac II tacrolimus assay showed the least M-I interference. Metabolite-II, which has a pharmacologic potency similar to the parent drug, showed a significant interference in the immunoassays and significant interference in radioreceptor assays. Metabolite III, which is pharmacologically inactive, produces 3-10% interference in the different assays if its presence in the blood is 6% of the parent drug. The total interference from these three metabolites was greater in the immunoassays than in the receptor assays. Receptor assays for tacrolimus provide results closer to the target value than do immunoassays.

Cross Reactions↗