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Biomedical subjects

K Thornton

Publications and source records attributed to K Thornton.

At least 19 recordsLinked to original sources
PubMed2001

An ERCC1 splicing variant involving the 5'-UTR of the mRNA may have a transcriptional modulatory function.

Human ovarian cancer cells and tissues were examined for the presence or absence of a 42-bp splicing variant of ERCC1 gene, and for a possible functional role of this 42-bp sequence. This specific sequence exists in exon I, the 5'-UTR of the gene. Loss of this 42-bp sequence was associated with increased ERCC1 mRNA expression, in an assessment of 121 ovarian cancer specimens (p2<10(-6)). In cells in tissue culture, the absence of the 42-bp segment was associated with a twofold increased ability to drive transcription in a Luciferase reporter system. Protein can be demonstrated in ovarian cancer cells based on EMSA analysis. Computer analysis shows that this 42-bp sequence contains several binding sites, including a core-binding domain for protein RFX1, transcriptional repressor. These preliminary results lay the groundwork in determination of potential roles for a negative regulatory element in NER repair pathway.

5' Untranslated Regions↗
PubMed2001

Dynamics of late-stage phase separation in crystalline solids.

The dynamics of Ostwald ripening in elastically stressed crystalline solids is determined through large-scale numerical simulations. Using the insight provided by the simulations, a theory for the dynamics of late-stage phase separation in elastically anisotropic homogeneous solids is developed. Both the theory and simulations show that for the systems considered elastic stress does not alter the exponent of the temporal power law for the average particle size but does affect the amplitude of the power law in a manner that is only a function of the symmetry of the particle morphology.

Journal Article↗
PubMed2000

Increased mRNA levels of xeroderma pigmentosum complementation group B (XPB) and Cockayne's syndrome complementation group B (CSB) without increased mRNA levels of multidrug-resistance gene (MDR1) or metallothionein-II (MT-II) in platinum-resistant human ovarian cancer tissues.

Tumor tissue specimens from human ovarian cancer patients were assessed for relative mRNA abundance levels of several genes thought to be involved in the development of in vitro drug resistance in this disease. Higher mRNA levels of Xeroderma pigmentosum group B (XPB), which links DNA repair with DNA transcription, and of Cockayne's syndrome group B (CSB), which is essential for gene-specific repair, were observed in tumor tissues that were clinically resistant to platinum-based chemotherapy, as compared with tissues from patients responding to therapy. In a cohort of 27 patients, mRNA levels of XPB averaged 5-fold higher in platinum-resistant tumors (P = 0.001); and for CSB, mRNA levels averaged 6-fold higher but with greater variability (P = 0.033). Concurrently, these platinum-resistant tumor tissues did not exhibit significantly higher mRNA levels for the MDR1 (multidrug-resistance) gene (P = 0.134) or of the metallothionein-II (MT-II) gene (P = 0.598). Since these platinum-resistant tumors also show higher mRNA levels of ERCC1 and XPA, platinum resistance appears to be associated with concurrent up-regulation of four genes (XPA, ERCC1, XPB, and CSB). These four genes participate in DNA damage excision activity, gene-specific repair, and linkage of DNA repair with DNA transcription. These data suggest that concurrent up-regulation of genes involved in nucleotide excision repair may be important in clinical resistance to platinum-based chemotherapy in this disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Domain growth in ternary fluids: A level set approach

We analyze phase separation in ternary systems in the asymptotic hydrodynamic regime when the volume fractions and concentrations are constant. The multiphase Navier-Stokes equations are solved using a level set method. A new projection method was developed to treat multiple junctions for systems with more than two phases. It is found that surface tension ratios can alter the growth mechanism of a minority phase in the presence of two majority phases. When the minority phase wets the interface of the majority phases the domain growth rate of all three phases is initially similar to that of a symmetric binary fluid but slows down at later times.

Journal Article↗
PubMed2000

Improvement/rehabilitation of memory functioning with neurotherapy/QEEG biofeedback.

This article presents a new approach to the remediation of memory deficits by studying the electrophysiological functioning involved in memory and applying biofeedback techniques. A Quantitative EEG (QEEG) activation database was obtained with 59 right-handed subjects during two auditory memory tasks (prose passages and word lists). Memory performance was correlated with the QEEG variables. Clinical cases were administered the same QEEG activation study to determine their deviations from the values that predicted success for the reference group. EEG biofeedback interventions were designed to increase the value (to normal levels) of the specific electrophysiological variable that was related to successful memory function and deviant in the subject. Case examples are presented that indicate the successful use of this intervention style in normal subjects and in subjects with brain injury; improvement cannot be fully explained by spontaneous recovery, given the time postinjury. Five cases (two normal, two subjects with brain injury, and one subject who had stereotactic surgery of the hippocampus for seizure control) are presented. Improvements ranged from 68% to 181% in the group of patients with brain injury, as a result of the interventions.

Adolescent↗
PubMed2000

Computer based analyses of the 5'-flanking regions of selected genes involved in the nucleotide excision repair complex.

We have previously observed that the mRNA of selected genes involved in nucleotide excision repair appear to be coordinately expressed in human tissues from patients with ovarian cancer, testicular cancer, malignant brain tumors, and other malignancies. Such genes include ERCC1, XPA, XPB, XPD, XPF, and XPG. Coordinate mRNA expression appears to be most impressive in non-malignant tissues. We therefore began to explore possible reasons why such coordinate expression should occur. DNA sequences for the above noted genes were obtained from GeneBank. Two different software programs were applied to the DNA sequence, to the area 5' to the start of exon I of each gene. Analyses were performed by computer. The length of the 5' area assessed, was based on previous reports that determined what portion of the genomic sequence comprised the 5' UTR of the promoter of the respective gene. Based on this approach, potential DNA binding sites for no less than three dozen proteins, were identified in the 5'-flanking region of each of the NER genes studied. For each gene, potential binding sites for activator proteins and for repressor proteins were identified. The 5'-flanking regions for each gene noted above, had binding sites in common for 14 proteins with transcription modulatory activity. Eleven of these proteins are known for activator activity; two are reported to have repressor activity, and one has both repressor and activator function. These data suggest a possible molecular basis for the previously observed coordinate mRNA expression of selected NER genes in human tissue specimens.

Adaptor Protein Complex alpha Subunits↗
PubMed1999

Purification, characterization, and crystallization of the distal BRCT domain of the human XRCC1 DNA repair protein.

The XRCC1 DNA repair protein contains two regions of approximately 100 amino acids each that share homology with the BRCT (BRCA1 carboxyl terminus) domain superfamily. These two regions of XRCC1 have been shown to interact independently with DNA ligase III and poly(ADP-ribose)polymerase as part of a mechanism involved in the repair of DNA single-strand breaks. To understand how these BRCT regions specify protein-protein interactions and contribute to DNA repair function, we have overexpressed and purified the distal BRCT domain of XRCC1 with the goal of structure determination. The cDNA encoding this BRCT region (X1BRCTb) was inserted into the pET29 bacterial expression vector; the polypeptide was expressed in mostly soluble form and then purified by anion-exchange and gel filtration chromatography. Crystallization screening with the purified material resulted in the formation of large bipyramidal crystals. Crystals formed within several hours at room temperature from salt solutions of ammonium sulfate. Crystals diffract to approximately 2.85 A and were found to be in space group P4(1)2(1)2 (or its enantiomorph P4(3)2(1)2) with unit cell dimensions a = 100.43 A, c = 105.62 A. Crystals of similar character have also been obtained after incorporation of selenomethionine during expression of the protein. Efforts are now under way to determine the molecular structure of the X1BRCTb domain. These studies are likely to give insight into the interaction between XRCC1 and DNA ligase III and into general structural features of BRCT domains that exist in many other proteins.

Base Sequence↗
PubMed1995

Intrathecal fentanyl prolongs sensory bupivacaine spinal block.

The purpose of investigation was to study the effect of intrathecal fentanyl on the onset and duration of hyperbaric bupivacaine-induced spinal block in adult male patients. Forty-three patients undergoing lower extremity or genitourinary surgery were enrolled to receive either 13.5 mg hyperbaric bupivacaine 0.75% + 0.5 ml CSF it, (Group I) or 13.5 mg hyperbaric bupivacaine 0.75% + 25 micrograms fentanyl it, (Group II) according to a randomized assessor-blind protocol. The onset and duration of sensory block were assessed by pinching the skin with forceps in the midclavicular line bilaterally every two minutes for first twenty minutes and then every five to ten minutes. Similarly, the onset and duration of motor block were assessed and graded at the same time intervals using the criteria described by Bromage. The time required for two sensory segment regression and sensory regression to L1 dermatome was 74 +/- 18 and 110 +/- 33 min vs 93 +/- 22 and 141 +/- 37 min in Groups I and II, respectively (P < 0.05). Intrathecal fentanyl did not enhance the onset of sensory or motor block, or prolong the duration of bupivacaine-induced motor spinal block. Fewer patients demanded pain relief in the fentanyl-treated group than in the control group in the early postoperative period (19% vs 59%; P < 0.05). Episodes of hypotension were more frequent in the fentanyl-treated group than in the control group (43% vs 14%; P < 0.05). We conclude that fentanyl, 25 micrograms it, prolonged the duration of bupivacaine-induced sensory block (sensory regression to L1 dermatone) by 28% and reduced the analgesic requirement in the early postoperative period following bupivacaine spinal block.

Adjuvants, Anesthesia↗
PubMed1994

Structure of glucagon-like peptide (7-36) amide in a dodecylphosphocholine micelle as determined by 2D NMR.

We have used 2D 1H NMR to determine the structure of glucagon-like peptide-1-(7-36) amide bound to a dodecylphosphocholine micelle. In this membranelike environment, the peptide hormone is shown to have a structure similar to that observed for glucagon. It consists of an N-terminal random coil segment (residues 1-7), two helical segments (7-14 and 18-29), and a linker region (15-17). The C-terminal helix is more stable than the N-helix as determined by amide proton exchange experiments. The C-terminal helix shows much larger alpha and amide proton upfield secondary shifts relative expected for a random coil conformation. This suggests a highly helical structure in this portion of the molecule. The C-terminal helix also has a much larger fraction of residues that are hydrophobic, presumably enhancing the interaction of this portion of the peptide with the micelle (or membrane). The structure refined from the NOESY data is not a uniform alpha-helix throughout residues 6-30. A uniform helix would not be perfectly amphiphilic since the hydrophobic face of the N-terminal portion of the helix is positioned in nearly perfect opposition to the hydrophobic face of the C-terminal portion. However, helical distortion around residues 15-17 allows a phase shift of the two helical segments to position nearly all of the hydrophobic residues (and none of the hydrophilic ones) on a single face of the distorted single helix as would be required to favorably interact with the hydrophobic portion of the micelle or membrane.

Amides↗
PubMed1994

Assessment of human exposure to chemicals from Superfund sites.

Assessing human exposure to chemicals from Superfund sites requires knowledge of basic physical, chemical, and biological processes occurring in the environment and specific information about the local environment and population in the vicinity of sites of interest. Although progress is being made in both areas, there is still a tremendous amount to be done. Participants at this meeting have identified several of the areas in need of greater understanding, and they are listed below. Movement of dissolved and volatile organics, especially NAPLs, in the subsurface environment. This includes study of the partitioning of compounds between NAPLs, air, water, and soil. Partitioning of volatilized chemicals between gaseous and aerosol components of the atmosphere. This includes understanding how these components influence both wet and dry deposition. Long-term movement from sediments into biota and how these affect chronic toxicity to sediment biota. Broad validation of PBPK models describing partitioning of compounds from sediment and water into fish. Reactions of chemicals sorbed to atmospheric particles. This includes application of laboratory models to real and varied atmospheric conditions. Interactions between biotic and abiotic transformations in soil and sediment. Applicability of physiological pharmacokinetic models developed in laboratory studies of experimental animals and clinical investigations of humans to environmental chemicals, concentrations, and routes of exposure in humans. Use of human and wildlife behavioral and biomonitoring information to estimate exposure. This includes better understanding of human variability and the applicability of information gathered from particular wildlife species. To successfully address these gaps in our knowledge, much more analytical data must be collected.(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants↗
PubMed1994

Directions and opportunities in health informatics in British Columbia.

The social changes, and changes in perceptions of the effectiveness of health care in British Columbia have resulted in a large number of recommendations in the report of the British Columbia Royal Commission on Health Care and Costs. Many of these recommendations have implications for health informatics. The British Columbia Government, in outlining a response, foresees a major change in the emphases of health care, which will involve four major areas of health informatics: network evolution, automation of the patient record, outcome- and other quality-related databases, and consumer health education. These themes are discussed, in the light of the opinions of academics, health care providers, and the health-informatics industry. The themes must be intercalated into the health informatics curriculum, to equip graduates for the challenges of B.C.'s changing health care system.

British Columbia↗
PubMed1993

Import, processing, and two-dimensional NMR structure of a linker-deleted signal peptide of rat liver mitochondrial aldehyde dehydrogenase.

Previous NMR studies (Karslake, C., Piotto, M. E., Pak, Y. M., Weiner, H., and Gorenstein, D. G. (1990) Biochemistry 29, 9872-9878) had shown that a 22-amino acid signal peptide of rat liver aldehyde dehydrogenase (ALDH) when bound to a micelle had two amphiphilic alpha-helices, one located at the N terminus and the other at the C terminus. It was shown that deletion of either helix caused the precursor protein not to be imported (Wang, Y., and Weiner, H., (1993) J. Biol. Chem. 268, 4759-4765). The two helices are separated by a Arg-Gly-Pro flexible "linker" region, and to test the role of this linker region in the import and processing of the precursor protein, we deleted it from the ALDH signal peptide and precursor protein. The 19-amino acid signal peptide of ALDH, to which has been added 3 residues at the C terminus and from which has been deleted the 3-residue flexible linker region, has been studied by two-dimensional NMR in a dodecylphosphocholine micelle. In this membrane-like environment the peptide contains a single alpha-helical segment that extends almost the entire length of the peptide. NH exchange experiments show residues on the hydrophobic face of the peptide to exchange much more slowly than those of the hydrophilic face. Combined with the previous study, these results suggest that precursor protein import simply requires a sufficiently long amphiphilic helix (or helices) to bind stably to the membrane. The N and C helices of native ALDH are only about 6-8 residues long; this represents only about two turns of a helix, and either helix on its own does not provide enough stabilization to ensure folding and binding to the membrane. The linker-deleted ALDH peptide contains a single helix of 12-14 residues that is long enough to provide a hydrophobic surface that can stably interact with the hydrophobic interior of the membrane. The function of the C helix in the native signal peptide is therefore to enhance the stability and binding of the N-terminal signal to the membrane. Significantly, unlike native ALDH precursor protein, the linker-deleted signal peptide precursor protein could no longer be processed after import into mitochondria. As explained by modeling of the alpha-helix and the NH exchange rate data, the precursor protein requires that the first several residues of the mature protein be part of the hydrophobic membrane associated face of the helix.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldehyde Dehydrogenase↗
PubMed1993

Plasma corticotropin-releasing hormone, beta-endorphin and cortisol inter-relationships during human pregnancy.

To investigate the dynamic relationships among corticotropin-releasing hormone (CRH), beta-endorphin (beta EP), cortisol and obstetric events during pregnancy, blood samples were collected from 193 women at 28 weeks, 38 weeks, during labour and on the second postnatal day. Cord blood at delivery was also obtained. We found that: (1) Maternal plasma CRH, beta EP and cortisol rose from 28 to 38 weeks. (2) During the third trimester maternal plasma CRH and beta EP were correlated (r = 0.30, p < 0.001). (3) During labour, no correlations were found among maternal plasma CRH, beta EP and cortisol. (4) Maternal CRH at labour and the duration of labour were not correlated. (5) Maternal plasma CRH tended to be higher in women who delivered early (more than seven days prior to estimated date of confinement [EDC]) relative to those who were on time (within seven days' EDC) or late (greater than seven days after EDC). (6) CRH in maternal plasma at labour and cord blood were correlated (r = 0.29, p < 0.05) as were maternal and fetal beta EP (r = 0.43, p < 0.001). (7) Fetal obstetric difficulty was correlated with fetal beta EP (r = 0.54, p < 0.001). Our findings support the hypothesis that maternal plasma CRH regulates maternal beta EP during the third trimester, but other factors are involved during labour and in response to maternal obstetric stress.

Adult↗
PubMed1992

Influence of basal androgen levels in euandrogenic women on glucose homeostasis.

OBJECTIVE: To evaluate possible relationships between insulin action and the normal variations of serum androgens in euandrogenic women. DESIGN: Prospective evaluation of insulin action in normal nonobese women using hyperglycemic and euglycemic hyperinsulinemic clamp techniques, correlating insulin action to serum testosterone (T), free T, androstenedione (A), and dehydroepiandrosterone sulfate (DHEAS). Statistical analysis used Spearman's rank correlation. SETTING: Yale University Clinical Research Center. PARTICIPANTS: Nonobese females with normal oral glucose tolerance tests, on no medications known to affect glucose metabolism, having the following range of serum androgen levels: T, 0.69 to 3.12 nmol/L; free T, 0.17 to 1.25 nmol/L; A, 2.48 to 11.31 nmol/L; DHEAS, 0.68 to 10.61 mumol/L. Total number of patients studied: hyperglycemic clamps, n = 58; euglycemic hyperinsulinemic clamps, n = 43. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Pancreatic insulin secretion in response to hyperglycemia and insulin action as assessed by insulin-mediated glucose utilization using the euglycemic, hyperinsulinemic clamp technique. RESULTS: We identified no significant correlation between serum androgens and either glucose uptake or insulin-mediated glucose utilization. Glucose-stimulated insulin release was negatively correlated with serum T and free T throughout the normal range of these hormones. CONCLUSION: We conclude that, within the normal range, variations of serum androgens are not correlated with changes in the response to insulin. It seems unlikely, therefore, that modest increases of serum androgens within the normal range are responsible for inducing insulin resistance.

Androgens↗
PubMed1992

Predictive equations for total lung capacity and residual volume calculated from radiographs in a random sample of the Michigan population.

BACKGROUND: Published predicted values for total lung capacity and residual volume are often based on a small number of subjects and derive from different populations from predicted spirometric values. Equations from the only two large studies gave smaller predicted values for total lung capacity than the smaller studies. A large number of subjects have been studied from a population which has already provided predicted values for spirometry and transfer factor for carbon monoxide. METHODS: Total lung capacity was measured from standard posteroanterior and lateral chest radiographs and forced vital capacity by spirometry in a population sample of 771 subjects. Prediction equations were developed for total lung capacity (TLC), residual volume (RV) and RV/TLC in two groups--normal and total. Subjects with signs or symptoms of cardiopulmonary disease were combined with the normal subjects and equations for all subjects were also modelled. RESULTS: Prediction equations for TLC and RV in non-smoking normal men and women were square root transformations which included height and weight but not age. They included a coefficient for duration of smoking in current smokers. The predictive equation for RV/TLC included weight, age, age and duration of smoking for current smokers and ex-smokers of both sexes. For the total population the equations took the same form but the height coefficients and constants were slightly different. CONCLUSION: These population based prediction equations for TLC, RV and RV/TLC provide reference standards in a population that has provided reference standards for spirometry and single breath transfer factor for carbon monoxide.

Adult↗
PubMed1982

Utility of the Behavior Problem Checklist with preschool children.

Determined the utility of the Behavior Problem Checklist with preschool children, a sample of 101 male and 103 female children initially rated on this scale. Ss ranged in age from 42 to 72 months and currently were enrolled in Maine Headstart programs. Sixty-six of these children also were assessed on a preschool rating system developed to assess hyperactivity and withdrawal. Results revealed that the conduct disorder and socialized delinquency dimensions correlated most highly with the hyperactivity scales, while the personality disorder and immaturity dimensions correlated most highly with the withdrawal dimensions. The BPC was found to be sensitive in differentiating clinical from nonclinical groups. These findings suggest that the Behavior Problem Checklist, although not specifically designed to assess preschool age children, may be effective with this population.

Child↗