Climate change. Hidden health benefits of greenhouse gas mitigation.
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Air Pollution↗
Biomedical subjects
D L Davis
Publications and source records attributed to D L Davis.
Boundary conditions on the partitioning of deaminatively generated benzyl cations.
Nitrogenous entity-separated ion pairs (NESIPs) containing benzyl cations, nitrogen gas, and pivalate anions were generated via thermal deamination of N-benzyl-N-nitrosopivalamide. Some decompositions were performed in methanolic solutions saturated with selected nucleophiles: acetate, azide, or cyanide ions. Trace amounts of benzyl cyanide and tolunitriles were observed; no corresponding products were detected in the acetate and azide cases. Other decompositions were performed in the absence of traditional solvent but in the presence of the nucleophilic salts; again only poor cyanide interception of the cation was observed. The poor showing of the nucleophilic ions, when present, is discussed in the context of the lifetime of the cation, effective nucleophilicity, and cage effects in deamination.
Journal Article↗
A GATA-6 gene heart-region-specific enhancer provides a novel means to mark and probe a discrete component of the mouse cardiac conduction system.
The transcriptional programs that specify the distinct components of the cardiac conduction system are poorly understood, in part due to a paucity of definitive molecular markers. In the present study we show that a cGATA-6 gene enhancer can be used to selectively express transgenes in the atrioventricular (AV) conduction system as it becomes manifest in the developing multichambered mouse heart. Furthermore, our analysis of staged cGATA-6/lacZ embryos revealed that the activity of this heart-region-specific enhancer can be traced back essentially to the outset of the cardiogenic program. We provide evidence that this enhancer reads medial/lateral and anterior/posterior positional information before the heart tube forms and we show that the activity of this enhancer becomes restricted at the heart looping stage to AV myocardial cells that induce endocardial cushion formation. We infer that a deeply-rooted heart-region-specific transcriptional program serves to coordinate AV valve placement and AV conduction system formation. Lastly, we show that cGATA-6/Cre mice can be used to delete floxed genes in the respective subsets of specialized heart cells.
Animals↗
Reassessment of the lethal London fog of 1952: novel indicators of acute and chronic consequences of acute exposure to air pollution.
This article develops and assesses novel indicators of respiratory and other morbidity and mortality following London's lethal smog in the winter of 1952. Public health insurance claims, hospital admission rates for cardiac and respiratory disease, pneumonia cases, mortality records, influenza reports, temperature, and air pollutant concentrations are analyzed for December-February 1952-1953 and compared with those for the previous year or years. Mortality rates for the smog episode from December 1952 to February 1953 were 50-300% higher than the previous year. Claims that the smog only elevated health risks during and immediately following the peak fog 5-9 December 1952 and that an influenza epidemic accounted fully for persisting mortality increases in the first 2 months of 1953 are rejected. We estimate about 12,000 excess deaths occurred from December 1952 through February 1953 because of acute and persisting effects of the 1952 London smog. Pollution levels during the London smog were 5-19 times above current regulatory standards and guidelines and approximate current levels in some rapidly developing regions. Ambient pollution in many regions poses serious risks to public health.
Acute Disease↗
Assessing the health benefits of urban air pollution reductions associated with climate change mitigation (2000-2020): Santiago, São Paulo, México City, and New York City.
To investigate the potential local health benefits of adopting greenhouse gas (GHG) mitigation policies, we develop scenarios of GHG mitigation for México City, México; Santiago, Chile; São Paulo, Brazil; and New York, New York, USA using air pollution health impact factors appropriate to each city. We estimate that the adoption of readily available technologies to lessen fossil fuel emissions over the next two decades in these four cities alone will reduce particulate matter and ozone and avoid approximately 64,000 (95% confidence interval [CI] 18,000-116,000) premature deaths (including infant deaths), 65,000 (95% CI 22,000-108,000) chronic bronchitis cases, and 46 million (95% CI 35-58 million) person-days of work loss or other restricted activity. These findings illustrate that GHG mitigation can provide considerable local air pollution-related public health benefits to countries that choose to abate GHG emissions by reducing fossil fuel combustion.
Adolescent↗
It's time to rethink dose: the case for combining cancer and birth and developmental defects.
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Adolescent↗
Development of porcine embryos in vitro: effects of culture medium and donor age.
We compared development of porcine embryos in three media and evaluated the effect of age of the donor on embryo development in vitro. In Exp. 1, embryos were collected from 35 postpubertal females on d 2 or 3 after onset of estrus. Embryos were cultured 144 h in Whitten's Medium (WM), North Carolina State University Medium-23 (NCSU-23), or Beltsville Embryo Culture Medium-3 (BECM-3) in 95% air: 5% CO2 at 39 degrees C. More (P < 0.01) embryos that were initially one cell or two cells developed to blastocysts when cultured in NCSU-23 (56%) and BECM-3 (43%) rather than in WM (7.5%). More (P < 0.01) embryos that were four cells at recovery developed to blastocysts in NCSU-23 (97%) than in BECM-3 (69%) or WM (69%). Blastocysts that developed from four-cell embryos cultured in BECM-3 had more (P < 0.01) nuclei than blastocysts that developed from four-cell embryos in the other two media. In Exp. 2, ovarian responses, fertilization rates, and in vitro embryo development in NCSU-23 and BECM-3 were compared for postpubertal (approximately 170-d-old) gilts vs gilts given exogenous gonadotropins at 102 d of age. Ovulation rate (P < 0.01), number of eggs recovered, and number of eggs fertilized per gilt (P < 0.001) were greater in the older gilts. The percentage of eggs fertilized, the number of unfertilized eggs, and the number of unclassifiable eggs were similar (P > 0.10) for both age groups. More (P < 0.10) blastocysts developed from embryos recovered from 170-d-old than from 102-d-old gilts, and more (P < 0.05) blastocysts developed in NCSU-23 than in BECM-3. Zona thicknesses and number of nuclei per embryo were similar (P > 0.10) for both ages. We conclude that embryos from prepubertal gilts do not have the same in vitro developmental potential as those from cyclic gilts. However, superior development of embryos in NCSU-23 from both 102-d-old and 170-d-old gilts indicates that media composition did not differentially affect embryos produced by younger vs older gilts.
Age Factors↗
Genetic analysis of intestinal cholesterol absorption in inbred mice.
A genetic mapping strategy was employed to identify chromosomal regions harboring genes that influence the absorption of intestinal cholesterol in the mouse. Analysis of seven inbred strains of male mice (129P3, AKR, BALB/c, C3H/He, C57BL/6, DBA/2, and SJL, all from Jackson Laboratories) revealed substantial differences in their abilities to absorb a bolus of cholesterol delivered by gavage. Crosses between high (AKR, 129) and low (DBA/2, SJL) absorbing strains revealed evidence for the presence of dominant genes that increase and decrease cholesterol absorption. Backcrosses between F1 offspring and parental strains (DBA/2xAKD2F1 and 129xSJL129F1) followed by linkage analyses revealed four quantitative trait loci that influenced cholesterol absorption. Analyses of recombinant inbred strains identified an additional three loci affecting this phenotype. These seven quantitative trait loci, which map to different chromosomes and are termed Cholesterol absorption 1-7 (Chab1-7) loci, together influence the absorption of intestinal cholesterol in mice and are likely to be involved in different steps of this complex pathway.
Animals↗
Genetic analysis of cholesterol accumulation in inbred mice.
Genetic linkage analysis in the laboratory mouse identified chromosomal regions containing genes that contribute to cholesterol accumulation in the liver and plasma. Comparisons between five inbred strains of mice obtained from the Jackson Laboratory (DBA/2, AKR, C57BL/6, SJL, and 129P3) revealed a direct correlation between intestinal cholesterol absorption and susceptibility to diet-induced hypercholesterolemia. This correlation was lost in the F1 generation arising from crosses between high- and low-absorbing strains. Linkage analyses in AKxD recombinant inbred strains and 129xSJL129F1 N2 backcross mice identified four quantitative trait loci (QTL) that influenced Liver cholesterol accumulation (Lcho1-4) and one locus that affected Plasma cholesterol accumulation (Pcho1). These loci map to five chromosomes and, with one exception, are different from the seven QTL identified previously that influence intestinal cholesterol absorption. We conclude that a large number of genes affects the amount of cholesterol absorbed in the small intestine and its accumulation in the liver and plasma of inbred mice.
Animals↗
Identification of ubiquitin as an immunophilin.
We have identified an 8.4 kDa minor immunophilin from calf thymus and Jurkat T cells as ubiquitin. It binds tacrolimus and sirolimus with K(d)'s of 0.8 and 0.08 nM, respectively. The binding of this protein to cyclosporin A is negligible. Binding of tacrolimus to two commercial sources of ubiquitin, a bovine product, and a recombinant human ubiquitin, was also demonstrated after HPLC purification of the purchased preparations.
Amino Acid Sequence↗
Analysis of the degradation of oligonucleotide strands during the freezing/thawing processes using MALDI-MS.
Synthetic oligonucleotide strands ranging from 5 to 25 units in length are commonly used as standards, probes, and templates in various bioanalytical applications. Until recently, their preparation, storage, and handling were regarded as unimportant, but this work provides valuable information to the contrary. The systematic degradation of oligonucleotide strands during sample preparation is investigated by repeatedly freezing/thawing short strands followed by matrix-assisted laser desorption ionization mass spectrometric (MALDI-MS) analysis. It is shown here that the longevity of an oligonucleotide strand is dependent on several factors including base composition, solution concentrations, and strand length as well as thawing conditions. Several trends in strand robustness were established. Our studies reveal that the robustness of strands is base-dependent: T-mer > A-mer > C-mer > G-mer. Likewise, an increase in the length of the strands increases the tendency of a sample to degrade. Another observation included that samples of mixed bases degrade according to structural conformations. All of these observations are attributed to the fact that the samples undergo degradation during sample/solvent isolation during freezing.
Base Sequence↗
An Nkx-dependent enhancer regulates cGATA-6 gene expression during early stages of heart development.
The evolutionarily conserved GATA-6 transcription factor is an early and persistent marker of heart development in diverse vertebrate species. We previously found evidence for a functionally conserved heart-specific enhancer upstream of the chicken GATA-6 (cGATA-6) gene and in the present study we used transgenic mouse assays to further characterize this regulatory module. We show that this enhancer is activated in committed precursor cells within the cardiac crescent and that it remains active in essentially all cardiogenic cells through the linear heart stage. Although this enhancer can account for cGATA-6 gene expression early in the cardiogenic program, it is not able to maintain expression throughout the heart later in development. In particular, the enhancer is sequentially downregulated along the posterior to anterior axis, with activity becoming confined to outflow tract myocardium. Enhancers with similar properties have been shown to regulate the early heart-restricted expression of the mouse Nkx2.5 transcription factor gene. Whereas these Nkx2.5 enhancers are GATA-dependent, we show that the cGATA-6 enhancer is Nkx-dependent. We speculate that these enhancers are silenced to allow GATA-6 and Nkx2.5 gene expression to be governed by region-specific enhancers in the multichambered heart.
Animals↗
Diabetes training for dietitians: needs assessment, program description, and effects on knowledge and problem solving.
Recent changes in management and medical nutrition therapy for diabetes mellitus have produced a need to retrain many practicing dietitians. To meet this need, a multidisciplinary group experienced in medical nutrition therapy and educational methods used a formal needs-assessment process to design a new training program. Sugar is Not a Poison (SNAP): The Dietitian's New Role in Diabetes Management is a 2 1/2-day program that uses written text, didactic presentation, and exercises that simulate patient encounters to accomplish 12 learning objectives. Program evaluations show high levels of participant satisfaction. Mean (+/- standard deviation) scores on pre- and postests of knowledge and problem solving were 69 +/- 13% and 86 +/- 9%, respectively (P < 0.01). The SNAP program needs assessment, training methods, and knowledge problem-solving test are relevant to all types of education programs in clinical dietetics.
Diabetes Mellitus↗
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↗
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↗
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↗
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↗
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↗