Characterization of a non-human primate model of drug-induced torsades de pointes.
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Animals↗
Biomedical subjects
D R Davis
Publications and source records attributed to D R Davis.
The effect of pseudouridine and pH on the structure and dynamics of the anticodon stem-loop of tRNA(Lys,3).
The anticodon stem-loop hairpin of tRNA(Lys,3) was synthesized and the solution structure determined by NMR spectroscopy. The hairpin is thermodynamically stabilized by pseudouridine as determined by UV Tm measurements, and the local loop structure is stabilized with base-stacking of the nucleosides in the anticodon loop 5' of the psi 39 nucleoside modification. The tRNA(Lys,3) hairpin also contains an A(+)-C base-pair that effectively reduces the size of the normal 7 nucleotide anticodon loop to 5 nucleotides and induces a change in the loop backbone conformation. The stabilizing effects of the A(+)-C base-pair and pseudouridine are only partially additive, suggesting that the conformational changes caused by each modification are not completely compatible. The structure of the anticodon loop is distinctly different from that seen for other tRNAs exemplified by tRNA(Phe), suggesting that the full complement of modified nucleosides present in tRNA(Lys,3) should significantly change the structure compared to the unmodified tRNA anticodon loop. The conformation of the loop has important implications for the role of nucleoside modification in codon-anticodon recognition and for utilization of tRNA(Lys,3) by HIV-1 as the natural reverse transcriptase primer.
Anticodon↗
Prevention of coronary heart disease with pravastatin.
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Age Factors↗
Conformational flexibility in RNA: the role of dihydrouridine.
In order to further understand the structural role of the modified nucleoside dihydrouridine in RNA the solution conformations of Dp and ApDpA were analyzed by one- and two-dimensional proton NRM spectroscopy and compared with those of the related uridine-containing compounds. The analyses indicate that dihydrouridine significantly destabilizes the C3'-endo sugar conformation associated with base stacked, ordered, A-type helical RNA. Equilibrium constants (Keq = [C2'-endo]/[C3'-endo]) for C2'-endo-C3'-endo interconversion at 25 degrees C for Dp, the 5'-terminal A of ApDpA and D in ApDpA are 2.08, 1.35 and 10.8 respectively. Stabilization of the C2'-endo form was shown to be enhanced at low temperature, indicating that C2'-endo is the thermodynamically favored conformation for dihydrouridine. DeltaH values show that for Dp the C2'-endo sugar conformation is stabilized by 1.5 kcal/mol compared with Up. This effect is amplified for D in the oligonucleotide ApDpA and propagated to the 5'-neighboring A, with stabilization of the C2'-endo form by 5.3 kcal/mol for D and 3.6 kcal/mol for the 5'-terminal A. Post-transcriptional formation of dihydrouridine therefore represents a biological strategy opposite in effect to ribose methylation, 2-thiolation or pseudouridylation, all of which enhance regional stability through stabilization of the C3'-endo conformer. Dihydrouridine effectively promotes the C2'-endo sugar conformation, allowing for greater conformational flexibility and dynamic motion in regions of RNA where tertiary interactions and loop formation must be simultaneously accommodated.
Drug Stability↗
Gluten-sensitive enteropathy in patients with insulin-dependent diabetes mellitus.
OBJECTIVE: To determine the prevalence of celiac disease in a cohort of patients with insulin-dependent diabetes mellitus and to describe the clinical characteristics of patients with coexistent disease. DESIGN: Prospective cohort study. SETTING: U.S. Army medical center. PATIENTS: 47 patients with insulin-dependent diabetes mellitus. MEASUREMENTS: Antiendomysial antibody testing was used to screen for celiac disease. The diagnosis of celiac disease required histologic evidence of villous atrophy and crypt hyperplasia and a positive antiendomysial antibody test result. In patients identified as having coexistent disease, complete blood counts, multiphasic biochemical testing, D-xylose absorption testing, and bone mineral density estimates were done. RESULTS: 3 of 47 patients with insulin-dependent diabetes mellitus (6.4%; 95% CI, 1.4% to 17.5%) had positive antiendomysial antibody test results and small-bowel biopsy specimens consistent with celiac disease. The 95% CI lies entirely above the estimated prevalence of celiac disease expected in the general U.S. population, which ranges from 0.02% to 0.1%. Mean bone mineral densities were 0.8 and 1.1 SD below age-, ethnicity-, and sex-matched controls in each of the 2 antiendomysial antibody-positive patients tested. Small bowel absorption was abnormal in 1 of the 2 patients tested by D-xylose. Anemia and hypoalbuminemia were not detected in any of the patients with coexistent disease. Only 1 of the 3 patients had symptoms of diarrhea. All patients were at or above their ideal body weights. CONCLUSIONS: Celiac disease appears to be more common among patients with insulin-dependent diabetes mellitus than in the general U.S. population (p less than 0.001). Two of the three patients with coexistent disease in this study had subclinical or latent celiac disease.
Adult↗
Detection of the angiotensin converting enzyme gene I/D polymorphism from extremely small volumes of stored serum.
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Base Sequence↗
Effect of wet and dry cellulose ring liners on setting expansion and compressive strength of a gypsum-bonded investment.
Effective setting expansion of gypsum-bonded investments is influenced by many variables. The purpose of this study was to determine the effect of using either water-saturated or dry cellulose ring lining material on (1) the fit of castings on a steel die and (2) the compressive strengths of investment cores using either type of liner. The mean gingival space in the water-saturated liner group was 0.241 +/- 0.048 mm and was 0.071 +/- 0.029 mm in the dry liner group (p < 0.001). The compressive strengths of investment cores from the dry liner group were 36.5% greater than those of cores from the water-saturated liner group. The results demonstrated that the use of dry liners may improve the fit of castings to dies.
Calcium Sulfate↗
M235-->T polymorphism of the angiotensinogen gene predicts hypertension in the elderly.
OBJECTIVE: To determine whether the M235-->T polymorphism (exon 2) of the angiotensinogen gene is associated with hypertension in elderly patients with isolated systolic hypertension [ISH: systolic blood pressure (SBP) > or = 160 mmHg, diastolic blood pressure (DBP) < 90 mmHg) or systolic-diastolic hypertension (SDH: DBP > or = 90 mmHg, SBP > or = 160 mmHg) compared with normotensive controls (SBP < 160 mmHg, DBP < 90 mmHg). DESIGN: A case-control study in 769 non-institutionalized, elderly (aged > or = 60 years; female:male ratio 0.85) residents of Dubbo, New South Wales. METHODS: Individuals were classified as having ISH (n = 171), having SDH (n = 218) and being normotensive controls (n = 366) with age and sex matching. MM, TT and MT genotypes were determined by a nested polymerase chain reaction strategy using DNA extracted from serum. The prediction of ISH or SDH by genotype or allele was examined in a multiple-logistic regression model that controlled for various confounders. RESULTS: SBP (mean +/- SD, mmHg)/DBP (mean +/- SD, mmHg) was 176 +/- 16/79 +/- 8 in the ISH group, 167 +/- 23/97 +/- 7 in the SDH group and 134 +/- 14/74 +/- 9 in the normotensive control group. The frequencies of M and T alleles in the normal population (0.69 and 0.31, respectively) were altered significantly in the ISH group (0.61 and 0.39, respectively; chi 2 = 6.0, P < 0.02) and the SDH group (0.62 and 0.38, respectively; chi 2 = 6.0, P < 0.02). The presence of the TT genotype predicted both ISH (odds ratio 1.9, 95% confidence interval 1.1-3.3) and SDH (1.7, 1.0-3.0) as did that of the T allele (ISH: 1.3, 1.0-1.7; SDH: 1.3, 1.0-1.7). CONCLUSIONS: The M235-->T polymorphism may be a marker for both forms of hypertension in the elderly. Whether the TT genotype represents a genetic risk factor for the development of hypertension in later life requires confirmation.
Aged↗
Rate-dependent effects of sematilide on ventricular monophasic action potential duration and delayed rectifier K+ current in rabbits.
Our objective was to define the actions of sematilide in rabbits and to assess the contribution of the delayed rectifier (IK) to rate dependence of action potential duration (APD) in rabbit ventricular myocardium. In studies in vivo, New Zealand White rabbits were used to obtain dose/response curves of the effects of sematilide on APD from contact monophasic action potentials (MAP), ventricular effective refractory period (VERP), and ECG. Sematilide or placebo was administered as an i.v. bolus followed by a 45-min infusion in the following cumulative manner: infusion 1 (1 mg/kg bolus + 8 micrograms/kg/min); infusion 2 (2 mg/kg + 20 micrograms/kg/min); and infusion 3 (7 mg/kg + 68 micrograms/kg/min). At each infusion level, VERP and APD at 75% repolarization (APD75) were measured during cardiac pacing between 200- and 400-ms cycle length (CL). Serum sematilide levels were analyzed by high-performance liquid chromatography (HPLC). In studies in vitro, sematilide's effects on the delayed rectifier were assessed in isolated rabbit ventricular myocytes by using patch-clamp techniques. Sematilide infusion in vivo resulted in stable serum levels of 1.3 +/- 0.5, 3.7 +/- 1.4, and 13.4 +/- 1.8 micrograms/ml during infusions 1, 2, and 3, respectively. Maximal effects occurred at infusion 2, such that at 400 ms CL, sematilide widened predrug APD75 (145 +/- 5 ms) by 27 +/- 4% (p < 0.001 vs. placebo), and at 200-ms CL, sematilide prolonged predrug APD75 (115 +/- 10 ms) by only 18 +/- 4% (p < 0.001 vs. placebo; p < 0.05 vs. 400-ms CL). Similar effects were observed in VERP. Sematilide enhanced rate dependence of APD and produced the same degree of APD prolongation at a given CL, during accommodation to and recovery from rapid pacing. Rabbit ventricular myocytes appeared to have at least two types of delayed rectifier. Sematilide selectively blocked IKr, and block was not relieved by repetitive stimulation. In conclusion, the APD-widening effect of sematilide was independent of previous pacing history. Sematilide had little influence on background processes likely responsible for shortening APD because of rapid repetitive stimulation.
Action Potentials↗
I/D polymorphism of the angiotensin-converting enzyme gene does not predict isolated systolic or systolic-diastolic hypertension in the elderly.
To determine whether insertion/deletion (I/D) polymorphism (intron 16) of the angiotensin converting-enzyme (ACE) gene is associated with isolated systolic hypertension (ISH: systolic blood pressure (BP) > or = 160, diastolic BP < 90 mm Hg) or systolic-diastolic hypertension (S-D hypertension: diastolic BP > or = 90 +/- systolic BP > or = 160 mm Hg) compared with normotensive controls (systolic BP < 160, diastolic BP < 90 mm Hg), we conducted a case-control study of 733 non-institutionalised, elderly (> or = 60 years) residents of Dubbo, NSW. Individuals were classified as: ISH (n = 167), S-D hypertension (n = 207) and normotensive control (n = 359) with age and sex matching. II, DD and ID genotypes were determined by a nested PCR strategy using DNA extracted from serum. The frequencies of D and I alleles in the control population (0.70 and 0.30 respectively) were not significantly different in the ISH group or the S-D hypertension group (chi 2: 1.7, P = 0.42). After adjustment for several potential confounders, neither genotype nor allele predicted ISH (II vs DD: odds ratio (OR): 1.06, 95% confidence interval (CI): 0.55-2.03; I vs D: 1.09, 0.82-1.46) or S-D hypertension (II vs DD: 1.19, 0.67-2.10; I vs D: 1.16, 0.89-1.52) in this elderly cohort. The I/D polymorphism of the ACE gene is not a marker for either form of hypertension in this large elderly sample.
Aged↗
Nested PCR for detection of the Met235-->Thr variant of the human angiotensinogen gene from small volumes of serum.
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Angiotensinogen↗
Stabilization of RNA stacking by pseudouridine.
The effect of the modified nucleoside pseudouridine (psi) on RNA structure was compared with uridine. The extent of base stacking in model RNA oligonucleotides was measured by 1H NMR, UV, and CD spectroscopy. The UV and CD results indicate that the model single-stranded oligoribonucleotides AAUA and AA psi A form stacked structures in solution and the CD results for AA psi A are consistent with a general A-form helical conformation. The AA psi A oligomer exhibits a greater degree of UV hypochromicity over the temperature range 5-55 degrees C, consistent with a better stacked, more A-form structure compared with AAUA. The extent of stacking for each nucleotide residue was inferred from the percent 3'-endo sugar conformation as indicated by the H1'-H2' NMR scalar coupling. This indirect indication of stacking was confirmed by sequential NOE experiments. NMR measurements as a function of temperature indicate that pseudouridine forms a more stable base stacking arrangement than uridine, an effect that is propagated throughout the helix to stabilize stacking of neighboring purine nucleosides. The N1-H imino proton in AA psi A exchanges slowly with solvent, suggesting a role for the extra imino proton in stabilizing the conformation of pseudouridine. These results show that the conformational stabilization is an intrinsic property of pseudouridine occurring at the nucleotide level. The characteristics of pseudouridine in these models are consistent with earlier studies on intact rRNA, indicating that pseudouridine probably performs the same stabilizing function in most structural contexts.
Magnetic Resonance Spectroscopy↗
Tau isoform expression and phosphorylation state during differentiation of cultured neuronal cells.
The axonal microtubule-associated protein, tau, is thought to play an important role in axonal growth and in the establishment of neuronal polarity. In adult human brain there are six alternatively spliced tau isoforms, which have different microtubule binding affinities in vitro. The tubulin-tau interaction is further modified by phosphorylation of tau and, compared to adult brain tau, both foetal brain tau and paired helical filament (PHF) tau, characteristic of Alzheimer's disease, are hyperphosphorylated. In vivo both the expression of tau isoforms and their phosphorylation states are developmentally regulated. In order to establish the correlation between the expression of tau isoforms and their pattern of phosphorylation, we have characterised these two features in several in vitro models of neuronal differentiation, including the human neuroblastoma cell lines, SK-N-SH, SH-SY5Y and IMR32 cells, rat PC12 cells and primary rat cortical neurones. Sensitive RT-PCR analysis revealed a different complement of tau isoforms in the different cell lines and neuritogenesis was associated mainly with an increase in the overall tau protein level with no apparent phosphorylation changes. A switch in tau isoform expression occurred only at the terminal stages of neuronal development, when it may be important in reinforcing the previously established axonal cytoarchitecture.
Alzheimer Disease↗
The phosphorylation state of the microtubule-associated protein tau as affected by glutamate, colchicine and beta-amyloid in primary rat cortical neuronal cultures.
The effects of the excitatory amino acid glutamate, the microtubule destabilizing agent colchicine, and beta 25-35-amyloid peptide on the phosphorylation state of tau were studied in rat cortical neurons in primary culture. Using immunocytochemistry and Western-blot analysis, we demonstrated that a proportion of tau in these cultures is normally highly phosphorylated, but most of this tau fraction is dephosphorylated after treatment of the cultures with glutamate or colchicine, but not with beta-amyloid; the glutamate- and colchicine-induced changes in tau phosphorylation commenced before cell death, as assessed by release of lactate dehydrogenase. Dephosphorylation of tau was readily revealed by using the monoclonal antibodies Tau.1 and AT8, which have phosphate-sensitive epitopes that both centre around serine-199 and -202 (numbering of the largest tau isoform). On Western blots and by immunocytochemistry, AT8 labelling strongly decreased after glutamate and colchicine treatments, whereas Tau.1 staining was more intense. Neurofilament monoclonal antibodies, including RT97, 8D8, SMI31 and SMI310, all additionally known to recognize tau in a phosphorylation-dependent manner, also demonstrated that glutamate and colchicine treatments of the cultures induced a dephosphorylation of tau. We also showed immunocytochemically that there is an increase in tau immunoreactivity in neuronal perikarya in response to glutamate and colchicine treatment, and this occurs concomitantly with the dephosphorylation of tau. Treatment of the primary rat cortical neuronal cultures with beta 25-35-amyloid peptide, under conditions which induce neuronal degeneration, did not induce a change in tau phosphorylation, and failed to act synergistically with glutamate to produce an increase in dephosphorylation of tau over that produced by glutamate treatment alone. These findings demonstrate that glutamate and colchicine induce tau dephosphorylation, as opposed to increased tau phosphorylation, which would be more indicative of Alzheimer-type neurodegeneration.
Amyloid beta-Peptides↗
Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993.
OBJECTIVE: To analyze temporal trends in acute respiratory distress syndrome (ARDS) fatality rates since 1983 at one institution. DESIGN: Cohort. SETTING: Intensive care units of a large county hospital. PATIENTS: Consecutive adult patients (> or = 18 years of age) meeting ARDS criteria were identified through daily surveillance of intensive care units (N = 918 from 1983 through 1993). The major causes were sepsis syndrome in 37% and major trauma in 25%; 37% had other risks. Sixty-five percent were male. The median age was 45 years (range, 18 to 92 years); 70% were younger than 60 years. MAIN OUTCOME MEASURE: Hospital mortality. RESULTS: Overall fatality rates showed no trend from 1983 to 1987, declined slightly in 1988 and 1989, and decreased to a low of 36% in 1993 (95% confidence interval, 25% to 46%). The crude rates were largely unchanged after adjustment for age, ARDS risk, and gender distribution. While patients both younger than 60 years and 60 years or older experienced declines in fatality rate, the larger decrease occurred in the younger cohort. In sepsis patients, ARDS fatality rates declined steadily, from 67% in 1990 to 40% in 1993 (95% confidence interval, 23% to 57%). The decline in sepsis-related ARDS fatality was confined largely to patients less than 60 years of age. Trauma patients and all other patients also experienced declines in fatality rates after 1987, although these trends were not as strong and consistent as in the sepsis population. CONCLUSIONS: In this large series, we observed a significant decrease in fatality rates occurring largely in patients younger than 60 years and in those with sepsis syndrome as their risk for ARDS. We are unable to determine the extent to which experimental therapies or other changes in treatment have contributed to the observed decline in the ARDS fatality rate. Institution-specific rates and temporal trends in ARDS fatality rates should be considered in clinical trials designed to prevent ARDS and the high mortality associated with this syndrome.
APACHE↗
Autoimmune cholangitis: a variant of primary biliary cirrhosis. Clinicopathologic and serologic correlations in 200 cases.
The term "autoimmune cholangitis" is used for a disease with clinical and pathologic features of primary biliary cirrhosis (PBC) but with negative anti-mitochondrial antibody (AMA) and positive anti-nuclear antibody (ANA) tests. In order to characterize autoimmune cholangitis and to determine whether this truly differs from PBC, we reviewed 200 cases morphologically consistent with PBC in which data on AMA and ANA status were available to us. Of these, 64 (32%) had a negative AMA, 114 (57%) had a positive ANA, and 40 (20%) had negative AMA and positive ANA (autoimmune cholangitis). The AMA-negative group was slightly younger on average (50 vs 55 years) than AMA positives (P < 0.05). There were no significant differences in gender (15.5% male overall), hepatic histopathology, or other laboratory tests between the groups of patients with any of the 4 possible combinations of AMA and ANA. Since the only consistently distinguishing feature among these patients is the autoantibody (AMA and ANA) profile, and they otherwise have virtually identical clinical and histopathologic features, autoimmune cholangitis can be considered to be the same as AMA-negative PBC.
Adult↗
Release of asbestos fibers during casting ring liner manipulation.
Civil lawsuits have been filed that allege wrongful deaths of at least one dentist and one dental technician from asbestos exposure. However, no known published scientific studies support such allegations. To assess what potential exposure could occur, air samples were collected while casting rings were lined with asbestos liner. Fibers were collected on filters and counted by use of phase-contrast microscopy and transmission electron microscopy. The concentrations of fibers 5 microns long or greater on all filters was less than allowed by federal guidelines. Based on this simulation the potential health risk from using asbestos ring liner seems low.
Air Pollution, Indoor↗
Characterization of canine humoral immune responses to outer surface protein subunit vaccines and to natural infection by Lyme disease spirochetes.
Canine antibody responses to Lyme disease subunit vaccines and to natural borrelial infection were investigated. Vaccines were formulated with QS21 and outer surface proteins A (OspA) and B (OspB) derived from Borrelia burgdorferi B31. Vaccines containing QS21 and the lipoproteins gave 4-fold higher IgG1 and 8-fold higher IgG2 antibody responses than without QS21. Antisera to lipidated OspA or OspB vaccines containing QS21 had high antiborrelial activity against isolates B31 and CA-2-87, similar to those with a vaccine containing both OspA and OspB. Only the combination vaccine induced antiborrelial activity against heterologous isolates 24008 Fr and Borrelia garinii G25. Nonlipidated OspA- and OspB-based vaccines with QS21 elicited lower antibody and antiborrelial activity than did lipidated OspA and OspB vaccines; 49% of naturally exposed dogs had low titers to OspA or OspB. Thus, vaccines using lipidated OspA, OspB, and QS21 could induce higher antiborrelial activity than did natural exposure.
Adjuvants, Immunologic↗