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Biomedical subjects

D Walker

Publications and source records attributed to D Walker.

At least 19 recordsLinked to original sources
PubMed1995

Evolutionary duplication of a hepatic control region in the human apolipoprotein E gene locus. Identification of a second region that confers high level and liver-specific expression of the human apolipoprotein E gene in transgenic mice.

We have identified a second hepatic control region (HCR-2) in the human apolipoprotein (apo) E gene locus that confers liver expression of the human apoE gene in transgenic mice. This HCR-2 sequence is located 27 kilobases downstream of the apoE gene and 10 kilobases downstream of the previously described liver-specific enhancer (HCR-1). Nucleotide sequence analysis of the HCR-2 region revealed a sequence that shares 85% identity to the functional 319-base pair domain of HCR-1. To test its activity, transgenic mice were prepared with a fusion construct containing a human apoE gene fragment, which is not normally expressed in the liver, ligated to a 632-base pair region containing the HCR-2 sequence. This construct resulted in high levels of liver-specific apoE transgene expression, indicating that HCR-2 can function as a hepatic enhancer and has an activity similar to that of HCR-1. Hence, these findings suggest that there are at least two hepatic control regions, HCR-1 and HCR-2, capable of controlling the liver expression of this human apolipoprotein gene locus.

Animals↗
PubMed1995

Structure of the hepatic control region of the human apolipoprotein E/C-I gene locus.

The specificity of expression in the liver of the human apolipoprotein (apo) E/C-I gene locus is determined by a hepatic control region (HCR) that is located 15 kilobases downstream of the apoE gene. DNase I footprint studies of this sequence using nuclear extracts identified a region of the HCR that is enriched in nuclear protein-binding sites. Nuclease analysis of chromatin revealed liver-specific DNase I-hypersensitive sites that were associated with this region, and additional liver-specific nuclease-sensitive sites associated with the apoE gene were identified. The HCR domain has a limited binding affinity for the nuclear scaffold. The specific domain required for liver expression was tested by ligating subfragments of the HCR to the apoE gene and examining their activity in transgenic mice. A segment of 319 nucleotides that contained several potential regulatory sequences was required for full activity of liver-specific transcription with shorter segments yielding much lower levels of expression in the liver. All constructs that contained a fully active HCR were expressed in approximately a copy-dependent manner, suggesting that transgene expression was independent of integration position. Taken together, the properties of the HCR are consistent with its function as a locus control region for the liver-specific expression of the apoE gene.

Animals↗
PubMed1995

Quality of life.

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Child↗
PubMed1995

A SecY homolog in Arabidopsis thaliana. Sequence of a full-length cDNA clone and import of the precursor protein into chloroplasts.

Proteins are translocated across the thylakoid membrane by two distinct pathways in higher plant chloroplasts, one of which is related to prokaryotic Sec-dependent translocation mechanisms. SecY is an essential, hydrophobic component of the membrane-bound translocase complex in bacteria, and we report here the nucleotide sequence of a full-length cDNA encoding a homolog of SecY from Arabidopsis thaliana. The predicted protein of 551 residues includes an amino-terminal extension of approximately 120 residues when compared with other SecY proteins. The deduced sequence of the mature protein, cpSecY, is 41% identical with SecY from Synechococcus and 33% identical with the Escherichia coli protein. The extension serves to target the protein into chloroplasts; transcription-translation of the cDNA yields a 58-kDa precursor protein which is imported into pea chloroplasts, processed to a product of 46 kDa, and targeted into the thylakoid membrane.

Amino Acid Sequence↗
PubMed1995

Central venous catheter practices: results of a survey.

BACKGROUND: The incidence of nosocomial bloodstream infections has increased twofold to threefold in the past decade, and central venous catheter infections account for about 90% of catheter-related nosocomial bloodstream infections. Many studies of risk factors for central venous catheter complications have been conducted, resulting in recommendations for preventive strategies, but few data are available regarding the frequency with which such strategies are employed in clinical practice. METHODS: A survey was conducted of persons attending a meeting of the National Association of Vascular Access Networks in New Orleans on September 25, 1992. The survey contained 15 questions related to central venous catheters regarding infection control measures, measures to maintain patency, and use of the catheter for obtaining blood specimens for diagnostic tests. RESULTS: Ninety-two persons from 24 states completed the questionnaire as representatives of 23 teaching hospitals, 21 nonteaching hospitals, and 48 home health agencies. Transparent dressings were used more frequently (88%) than cotton gauze (27%). Alcohol and povidone-iodine solutions were the most frequently used antiseptics. Antimicrobial ointment was used by fewer than half; of these 86% used povidone-iodine and 26% used polymyxin-neomycin-bacitracin. Heparin flushes were still being used by 97% to maintain patency. Most (82%) used central venous catheters to draw blood cultures; of these, 68% drew only qualitative cultures and 32% drew quantitative cultures in addition to or instead of qualitative cultures. CONCLUSIONS: Significant diversity of practice was documented among the health care organizations represented in this survey. Some of the practices documented in this survey have been associated with higher rates of bloodstream infection; this may partially explain the observed increase during the past decade in the incidence of nosocomial bloodstream infections.

Anti-Infective Agents, Local↗
PubMed1995

A comparison of mtDNA restriction sites vs. control region sequences in phylogeographic assessment of the musk turtle (Sternotherus minor).

A total of nearly 800 base pairs of mitochondrial DNA sequence was assayed in each of 52 musk turtles (Sternotherus minor) collected across the species' range in the south-eastern USA. About one-half of the sequence information in effect was accessed by conventional recognition-site assays of the entire mtDNA molecule; the remainder came from direct sequence assays of a normally hypervariable 5' section of the noncoding control region. The two assay methods produced essentially nonoverlapping sets of variable character states that were compared with respect to magnitudes and phylogeographic patterns of mtDNA variation. The two assay procedures yielded nearly identical outcomes with regard to: (a) total levels of species-wide mtDNA genetic variation; (b) mean levels of within-locale variation; (c) extremely high population genetic structure; (d) a phylogenetically significant separation of samples from the north-western half of the species' range vs. those in the south-eastern segment; and (e) considerably lower genetic variability within the north-western clade. The micro- and macro-phylogeographic mtDNA patterns in the musk turtle are consistent with a low-dispersal natural history, and with a suspected longer-term biogeographic history of the species, respectively.

Animals↗
PubMed1995

Clinical relevance of mutations in the precore genome of the hepatitis B virus.

A stop codon in the precore genome of the hepatitis B virus (HBV) in anti-HBe positive HBV carriers may be associated with a more progressive form of HBV infection. Earlier studies, however, were mainly performed in patients from the Mediterranean area who had severe infection. The aim of this study was to evaluate the prevalence of precore mutants in an unselected population living in northern Europe. Twenty of 42 of these patients are infected predominantly with a virus strain, which has the typical stop codon in the precore genome, characterised by a mutation at base 83. In six patients there was an additional G to A mutation at base 86 of the precore genome. Statistical analysis showed no difference between the patients with or without a stop codon in the precore genome. When patients with a double mutation at base 83 and 86 of the precore genome were compared with the other anti-HBe positive HBV carriers, however, the corresponding clinical data were worse. Therefore we suggest, that it is not the stop codon in the precore gene itself, but the occurrence of a double mutation at bases 83 and 86, which is associated with a more severe course of disease in anti-HBe positive HBV carriers.

Adult↗
PubMed1995

Technical note: low density contrast in upper abdominal computed tomography.

We describe the use of a fat-based low density oral contrast agent in computed tomography (CT) of the upper abdomen. It has a CT number of -71 Hounsfield units (HU) and allows excellent visualization of the bowel wall and adjacent structures as well as reducing the artefacts seen with iodinated high density contrast.

Abdominal Neoplasms↗
PubMed1994

Best's vitelliform dystrophy (VMD2) maps between D11S903 and PYGM: no evidence for locus heterogeneity.

Vitelliform macular dystrophy, also known as Best's disease (BD), is an autosomal dominant disorder typically characterized by an accumulation of yellowish material in the macular area. The disease is slowly progressive and eventually results in atrophy of the retinal pigment epithelium and photoreceptor cells, thus severely impairing central vision. The biochemical defect underlying this condition is unknown. More recently, the BD locus (VMD2) was mapped to chromosome 11 by genetic linkage to microsatellite markers at D11S871 and INT2. In the present study, we report a detailed genetic analysis in three multigeneration Best's disease families using eight microsatellite markers spanning approximately 26 cM around the putative BD locus. We demonstrate linkage between Best's disease and the markers used. Furthermore, haplotype analysis in our unrelated Best's disease families identified three distinct haplotypes associated with the disease, strongly suggesting independent origins of the BD mutation. Finally, we characterized two recombinant BD chromosomes that significantly refine the location of the disease gene to a 3.7-cM interval between markers at D11S903 and PYGM. PCR-hybrid mapping sublocalized this interval to the pericentromeric region of chromosome 11.

Chromosome Mapping↗
PubMed1994

QRST changes during and after percutaneous transluminal coronary angioplasty.

This study reports preliminary results on 45 patients who underwent percutaneous transluminal coronary angioplasty (PTCA); 120-lead data (including the 12-lead standard electrocardiogram [ECG]) were recorded before, during, and after balloon inflation. Twenty-one patients underwent PTCA for left anterior descending coronary disease, 13 for right coronary artery disease, and 10 for left circumflex; 1 patient had combined left anterior descending and right coronary artery disease. In each patient, voltage data recorded during the various phases of the procedure were compared with the patient's own baseline data. In 18 patients, 120 leads were also recorded 24 hours after PTCA. In this study, the usefulness of the standard 12-lead ECG was investigated in locating the coronary artery being occluded, in elucidating the mechanisms of the QRS changes, and in identifying changes occurring 24 hours after completion of the procedure. Results indicate that the observation of ST elevation in the 12-lead ECG may lead to ambiguous interpretation. Also, limiting observation to ST-T patterns alone instead of including QRS changes further hampers correct identification of the involved vessel. QRS modifications during inflation are interpreted as conduction disturbances, although other mechanisms are evoked: study of surface maps may contribute to the understanding of these mechanisms. Changes present 24 hours later are visible in the standard leads, but again, in the absence of the thoracic potential distribution, these are difficult to interpret. These changes were different from those observed after cessation of inflation at the end of the procedure. It is hypothesized that next-day changes may reflect reperfusion injury and/or represent myocardial stunning. Presence of injury and reversibility of changes require further investigation. Also, biochemical markers such as creatine kinase-MB mass, creatine kinase-MB activity, myoglobin, and troponin-T may help elucidate the significance of these findings.

Angioplasty, Balloon, Coronary↗
PubMed1994

Effect of hyperthermia on uterine and umbilical blood flows in pregnant sheep.

Uterine and umbilical blood flows were measured in pregnant sheep (125-142 days gestation) under normothermic and hyperthermic conditions using the Fick principle with [14C]antipyrine as the indicator. Exposure of the sheep to an ambient temperature of 43 +/- 1 degrees C (25-30% relative humidity) for 8 h increased maternal and fetal core temperatures 1.19 +/- 0.15 and 1.39 +/- 0.12 degrees C respectively. Maternal hyperventilation caused a significant decrease of both maternal and fetal arterial partial pressure of CO2 (Pa,CO2) and increase of arterial pH. Uterine blood flow increased significantly during the hyperthermia (+54.2 +/- 14.1%), the increase being correlated with the magnitude of the decrease of maternal Pa,CO2 (r = -0.84, P < 0.05) but not with the increase of maternal core temperature. The increase of uterine blood flow was not associated with a concomitant increase in the placental clearance of [14C]antipyrine, a result which could arise if the increase of blood flow was non-placental (i.e. did not occur within the cotyledons), or occurred through uterine arteriovenous shunts during the period of heat stress. Hyperthermia was not associated with a significant change of umbilical blood flow, placental transfer of glucose, or fetal glucose uptake. Since the loss of heat from the fetus occurs mainly across the placenta, we speculate that the apparent increase of uterine blood flow during maternal hyperthermia has an adaptive significance by maintaining conductive heat flux in a fetomaternal direction, even though cotyledonary (placental) blood flows did not increase.

Animals↗
PubMed1994

Does genetic anticipation occur in familial rheumatoid arthritis?

OBJECTIVE: To determine if there is evidence for genetic anticipation in rheumatoid arthritis (RA) by analysing the possibility that parental disease status and age at proband conception influence the age of onset and disease severity of the proband. METHOD: RA outpatients were identified and data were also taken from Newcastle multicase RA pedigrees. Comparisons of age of onset and parental age at proband conception were made for pedigrees grouped according to the disease status of the parents. Correlation coefficients and linear regression models were calculated for the age of RA onset in the probands. Measures of disease severity were compared in RA mother-proband pairs. RESULTS: The results were similar in both the outpatient (n = 153) and multicase pedigree (n = 15) samples. Significant results were confined to pedigrees in which the mother had RA (20 of the outpatient probands and seven of the multicase group). Probands in these sibships had a younger age of RA onset than their affected mothers (38.3 years (95% confidence interval (CI) 33.8 to 42.8) versus 53.7 (47.3 to 60.0) (p = 0.002) in the outpatient sample; 32.4 years (25.3 to 39.6) versus 43.4 years (29.0 to 57.9) (p = 0.1) in the multicase pedigrees). In the maternal RA group, both the maternal and paternal age at proband conception showed significant negative correlations (r = -0.65, p = 0.002 and r = -0.60, p = 0.005, respectively in the outpatient sample) and linear regression coefficients with age of proband disease onset. In seven affected mother-proband pairs, the probands had a tendency to more severe disease, despite shorter disease duration and younger age. CONCLUSIONS: This preliminary analysis has suggested that within pedigrees in which the mother has RA, the features of genetic anticipation and observations consistent with premutation models may prevail.

Adolescent↗
PubMed1994

Enhanced glucose oxidation in exercise-induced myocardial ischemia.

BACKGROUND: In animal models, dichloroacetate (DCA) facilitates recovery from severe myocardial ischemia by stimulating glucose oxidation. OBJECTIVE: To evaluate the acute efficacy of DCA as a metabolic anti-ischemic intervention in patients with coronary artery disease (CAD) and exercise-induced myocardial ischemia in a clinical trial. METHODS: Double-blind, randomized, crossover comparison of single dose (50 mg/kg intravenously) DCA versus placebo on clinical and electrocardiographic variables in seven patients with single vessel CAD and 34 patients with multiple vessel CAD during standard dynamic exercise testing. RESULTS: Blood pressure did not differ with placebo or DCA but mean heart rate was higher with DCA at rest (62 versus 59, P < 0.004) and at 5 mins of recovery (78 versus 75, P < 0.02). Exercise duration averaged 538 s with DCA and 534 s with placebo (not significant). Chest pain occurred in 14 patients in both tests, clinical ST depression occurred, in 34 placebo tests and 37 DCA tests (not significant). Body surface potential maps (BSPM) of the decrease in the area under the ST curve from rest to peak exercise averaged -5096 microV's with DCA and -5159 microV's with placebo (not significant). BSPM at 1 and 5 mins postexercise also showed no differences in rate of ST integral recovery. CONCLUSIONS: In the transient regional model of human myocardial ischemia induced by dynamic exercise, the acute administration of the pyruvate dehydrogenase agonist DCA was not associated with clinical or electrocardiographic moderation of, nor accelerated recovery from, ischemia. Whether DCA or metabolically similar agents that enhance oxidative metabolism are beneficial in other ischemic settings, such as the no-flow states of acute ST elevation myocardial infarction or angioplasty, requires further systematic evaluation.

Adult↗