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Biomedical subjects

J A Bell

Publications and source records attributed to J A Bell.

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

Randomised comparison of antero-lateral versus antero-posterior paddle positions for DC cardioversion of persistent atrial fibrillation.

We designed a prospective, randomised, single-blind trial to compare the relative efficacy of antero-lateral versus antero-posterior paddle positions for DC cardioversion of persistent atrial fibrillation. A total of 59 patients were randomised to cardioversion using standard gel pads placed either in the antero-lateral (AL) or antero-posterior (AP) positions. The first synchronised shock was given at 360 J; if this was unsuccessful, a second shock of 360 J was given in the alternative position. We compared cardioversion success rate and energy requirements with each strategy. With the first 360 J DC shock, a significantly greater proportion of patients were restored to sinus rhythm from the antero-lateral position (18/30) compared to the antero-posterior position (10/29) (P=0.048). For those patients remaining in atrial fibrillation, there was no difference in the proportions cardioverted from the antero-lateral position (4/19) compared to the antero-posterior position (5/12) with the second 360 J DC shock (P=0. 22). The total cardioversion success rate was 23/30 (77%) for antero-lateral followed by antero-posterior shocks compared to a success rate of 14/29 (48%) for antero-posterior followed by antero-lateral shocks, and this difference was significant (P=0.024). There was no significant difference in the mean energy delivered for patients randomised to an initial antero-lateral shock (504 J), compared to patients given an initial antero-posterior shock (583 J) (P=0.1). We conclude that the antero-lateral paddle position appears more effective for DC cardioversion of persistent atrial fibrillation.

Aged↗
PubMed2000

A circular mitochondrial plasmid incites hypovirulence in some strains of Cryphonectria parasitica.

In the chestnut-blight fungus Cryphonectria parasitica, a plasmid, pCRY1, occurs in the mitochondria of several strains isolated at various locations in the northeastern United States and Canada. The monomer of this plasmid is a 4.2-kb circular double-stranded DNA that has no detectable sequence homology with the 160-kb mitochondrial DNA of Ep155, a standard virulent laboratory strain of C. parasitica. The circular nature and oligomeric characteristics of the plasmid were deduced from the heterogeneous size of plasmid DNA molecules as detected by one- and two-dimensional gel-electrophoresis, the nature and alignment of restriction fragments, and the lack of detectable termini in the nucleotide sequence. The cytoplasmic location of the plasmid was deduced from its co-purification with mitochondria, uniparental (maternal) transmission in sexual crosses, dissociation from the nuclei of the donor strain during its horizontal transfer between vegetatively compatible strains through hyphal anastomoses, and mitochondrial codon usage (UGA = Try). The pCRY1 plasmid contains a long open reading frame that is transcribed and potentially encodes a unique 1214 amino-acid, B-family DNA polymerase similar to those encoded by the LaBelle and Fiji circular mitochondrial plasmids of Neurospora. In this subgroup of proteins, the DTD motif characteristic of B-family DNA polymerases is replaced by TTD. Amino-acid motifs related to those that are characteristic of the 3'-->5' exonuclease domains of B-family DNA polymerases have been located in the amino-terminal portion of the proteins. A comparison of isogenic plasmid-free and plasmid-containing cultures indicates that pCRY1 is an infectious agent that effects a reduction in the pathogenicity of some, but not all, strains of C. parasitica.

Amino Acid Sequence↗
PubMed2000

A comparative transcript map and candidates for mutant phenotypes in the Tyrp1 (brown) deletion complex homologous to human 9p21-23.

The mouse Tyrp1 deletion complex is a valuable resource for high-resolution mapping of genes and phenotypes to the central region of Chromosome (Chr) 4. The distal part of the complex is homologous to human Chr 9p21-23, and we have used the available radiation hybrid maps to identify human transcripts in the region. We localize seven genes to a human YAC contig that spans the full extent of the distal deletion complex and show that the mouse homologs of four of these, including Cer1, map within the complex. On the basis of location and/or expression, we exclude genes as candidates for several known phenotypes in the region and identify a candidate transcript for the neonatal lethal phenotype l(4)Rn2.

Animals↗
PubMed2000

c-erbB-4 protein expression in human breast cancer.

The Type 1 family of growth factor receptors includes epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3 and c-erbB-4. Overexpression of the first two members is associated with poorer prognosis in patients with breast carcinoma. In this study we examined the expression of c-erbB-4 protein using the monoclonal antibody HFR-1. A total of 127 consecutive cases of primary operable invasive breast carcinoma presenting between 1975 and 1977 were studied. All patients were managed by simple mastectomy or conservation surgery with radiotherapy and no adjuvant therapy given. Long-term follow-up was maintained. Routine, formalin-fixed, paraffin-embedded tumour samples were used and sections were stained immunohistochemically using the Duet StreptABC method. Immunoreactivity was classified using a simple semi-quantitative scoring method. Protein expression was generally low but definite positive cytoplasmic, membranous and nuclear reactivity was identified in 58%, 41% and 25% of cases respectively. Expression at all three sites demonstrated significant inverse associations were histological grade. In addition, membrane accentuation correlated inversely with the Nottingham Prognostic Index (NPI), while cytoplasmic reactivity showed a positive association with c-erbB-3 expression. No significant associations were found with disease-free interval or survival. The results of this study demonstrate that higher levels of c-erbB-4 protein expression are associated with a more differentiated histological phenotype in contrast to the other members of the Type 1 family. Larger series with extended follow-up will be required to ascertain definitively the prognostic value of c-erbB-4 expression in breast carcinoma.

Adult↗
PubMed2000

Randomised double blind trial of oral versus intravenous flecainide for the cardioversion of acute atrial fibrillation.

OBJECTIVE: To investigate whether an oral loading dose of flecainide is as safe and effective as intravenous flecainide for the cardioversion of acute atrial fibrillation. DESIGN: Prospective, randomised, double blind, double placebo study. SETTING: Cardiac care unit of a large district general hospital in the UK. PATIENTS AND METHODS: 79 patients presenting with symptomatic acute atrial fibrillation: patients were given either intravenous flecainide (n = 39) or a solution of oral flecainide (n = 40), with appropriate placebos. All patients were heparinised during the study. PRIMARY OUTCOME MEASURES: Safety; mean time to cardioversion; proportion of patients restored to sinus rhythm at two hours and eight hours after treatment. Analysis was by intention to treat. RESULTS: There were no differences in baseline characteristics between the oral and intravenous groups. Both forms of flecainide were well tolerated, with no adverse clinical events during the study. The mean time to cardioversion was 110 minutes in the oral group and 52 minutes in the intravenous group (p = 0.002). Two hours after treatment, 27 of the 40 patients in the oral group (68%) and 25 of the 39 in the intravenous group (64%) had reverted to sinus rhythm (p = 0.74). Eight hours after treatment, 30 patients in the oral group (75%) and 28 in the intravenous group (72%) had reverted to sinus rhythm (p = 0.76). CONCLUSIONS: Intravenous flecainide restored sinus rhythm more rapidly than oral flecainide, but at two hours and eight hours after treatment there was no difference in the proportion of patients cardioverted by the two approaches. These results suggest a role for oral loading doses of flecainide in the treatment of acute or symptomatic paroxysmal atrial fibrillation.

Acute Disease↗
PubMed1999

An immunohistochemical examination of the expression of E-cadherin, alpha- and beta/gamma-catenins, and alpha2- and beta1-integrins in invasive breast cancer.

This study examines the expression of the cell-cell adhesion molecules E-cadherin and its associated proteins, the catenins and the matrix-cell adhesion molecules beta1- and alpha2-integrins, in primary invasive breast carcinoma. Expression was assessed immunohistochemically on frozen sections by semi-quantitative scoring of the intensity and proportion of immunoreactivity in 55 cases. Associations with each other and with other histological and prognostic features and survival were sought. There was a significant association between loss of E-cadherin expression and loss of alpha- and beta/gamma-catenin immunostaining. In 20 per cent of cases, membranous immunoreactivity with E-cadherin antibody was absent. Absent cytoplasmic expression of alpha- and beta/gamma-catenins was seen in 24 and 22 per cent of breast cancers, respectively. The intensity of reactivity with E-cadherin showed a significant association with histological grade (p=0.002) and tumour type (p<0.001). Lobular carcinomas frequently showed loss of expression of E-cadherin, as reported elsewhere; loss of catenin expression was also found in these tumours. alpha-catenin intensity also showed a relationship with grade (p=0.008) and with oestrogen receptor (ER) status (p=0.006). beta/gamma-catenin expression was not associated with other known prognostic factors. Forty-nine per cent and 42 per cent of cases showed no membrane immunostaining with beta1- and alpha2-integrin, respectively, and co-ordinated loss of beta1- and alpha2-integrin expression was found. Both beta1- and alpha2-integrin expression were associated with histological grade (p=0.003 and p=0.031, respectively) and beta1 immunoreactivity with tumour type (p=0.010). None of the variables examined showed a statistically significant association with tumour size or lymph node stage, or with overall survival, although a trend was seen (p=0.087) towards poorer survival of patients with tumours with absent or weak expression of beta1-integrin. The expression of these markers is of biological interest, but appears to be of little additional use in predicting clinical behaviour.

Adult↗
PubMed1999

Ferret nutrition.

The unusually short intestinal tract of ferrets and closely related mustelids lacks a cecum and ileocolic valve. As a result, the transit time of ingesta in these carnivores is very rapid compared with other animals, and their food is inefficiently digested. Although the precise nutritional requirements of ferrets have not been determined by feeding defined diets, information has been compiled from experience feeding commercial and analyzed homemade diets to breeding ferrets, fitch, and mink at all stages of their lives. The requirements of spayed or neutered pet ferrets are met by allowing them constant access to drinking water and a palatable, pelleted, or extruded, 90% dry matter, premium cat or ferret food that, as fed, contains at least 15% fat and 30% high quality, meat source protein, less than 30% carbohydrates, and approximately 4 Kcal of metabolizable energy per gram. Lower density diets with more carbohydrate and less protein are associated with poor reproductive performance and growth and greater susceptibility to infectious and metabolic diseases.

Animal Nutritional Physiological Phenomena↗
PubMed1999

Utility of hepatocytes to model species differences in the metabolism of loxtidine and to predict pharmacokinetic parameters in rat, dog and man.

1. The metabolism of loxtidine (1-methyl-5-[3-[3-[(1-piperidinyl) methyl] phenoxy] propyl] amino-1H-1,2,4-triazole-3-methanol) was studied in freshly isolated rat, dog and human hepatocytes. Metabolism in vitro was comparable with previously available in vivo data in all three species with the marked species differences observed in vivo being reproduced in the hepatocyte model. 2. The major route for the metabolism of loxtidine by rat hepatocytes was N-dealkylation to form the propionic acid and hydroxymethyl triazole metabolites. A minor metabolic route was the oxidation of loxtidine to a carboxylic acid metabolite. The major route of metabolism for loxtidine in dog hepatocytes was glucuronidation with oxidation to the carboxylic acid metabolite being of minor importance. Incubation of loxtidine with human hepatocytes resulted in the drug remaining largely unchanged but with the carboxylic acid metabolite being produced in minor amounts. 3. In vitro studies were undertaken with rat, dog and human hepatocytes to determine the Michaelis-Menten parameters Vmax and Km for the sum of all the metabolic pathways. These kinetic parameters were used to calculate the intrinsic clearance of loxtidine. Using appropriate scaling factors, the predicted in vivo hepatic clearance was then calculated. The predicted intrinsic clearances were 51.4 +/- 12.4, 8.0 +/- 0.8 and 1.0 +/- 0.6 ml/min/kg for rat, dog and human hepatocytes respectively. These data were then used to calculate hepatic clearances of 24.5, 3.1 and 0.2 ml/min/kg for rat, dog and man respectively. 4. In vivo hepatic and intrinsic clearances for loxtidine were determined in rat, dog and human volunteers. The hepatic clearances of loxtidine were 26.6, 6.6 and 0.4 ml/min/kg in rat, dog and man respectively and intrinsic clearances were 58.5, 18.6 and 2.0 ml/min/kg in rat, dog and man respectively. 5. The present studies demonstrate that the hepatocyte model may be a valuable in vitro tool for predicting both qualitative and quantitative aspects of the metabolism of a drug in animals and man at an early stage of the drug development process.

Adult↗
PubMed1999

X-ray crystal structures of a severely desiccated protein.

Unlike most protein crystals, form IX of bovine pancreatic ribonuclease A diffracts well when severely dehydrated. Crystal structures have been solved after 2.5 and 4 days of desiccation with CaSO4, at 1.9 and 2.0 A resolution, respectively. The two desiccated structures are very similar. An RMS displacement of 1.6 A is observed for main-chain atoms in each structure when compared to the hydrated crystal structure with some large rearrangements observed in loop regions. The structural changes are the result of intermolecular contacts formed by strong electrostatic interactions in the absence of a high dielectric medium. The electron density is very diffuse for some surface loops, consistent with a very disordered structure. This disorder is related to the conformational changes. These results help explain conformational changes during the lyophilization of protein and the associated phenomena of denaturation and molecular memory.

Animals↗
PubMed1999

Pregnancy toxemia in the European ferret (Mustela putorius furo).

BACKGROUND AND OBJECTIVE: Pregnancy toxemia may lead to appreciable mortality among jills and their offspring. The objective of this report was to increase awareness of the disease, its likely cause, and practical prevention and treatment measures. METHODS: Ten cases of pregnancy toxemia were evaluated. Jills were in late gestation (mean, 38 days; range, 34 to 42 days) and had large litters (mean, 11.5 kits; range, 7 to 15 kits). RESULTS: The most common clinical signs of disease were lethargy, inappetence, dehydration, and excess shedding. Hematologic and clinical biochemical abnormalities included anemia (4 of 8 jills tested), hypoproteinemia (5 of 7), azotemia (7 of 7), hypocalcemia (5 of 6), hyperbilirubinemia (3 of 3), and high liver enzyme activities (6 of 6). Two jills were found dead; two jills were euthanized, six received supportive treatment, and cesarean section was performed on five. The three jills that survived tended to have less pronounced azotemia, hypoproteinemia, and liver enzyme activity increases and were not anemic. Hepatic lipidosis was observed grossly in all jills that died and was confirmed by histologic examination in four jills. CONCLUSIONS: Pregnancy toxemia in ferrets resembles metabolic diseases in several other animal species and requires aggressive treatment, including supportive care, nutritional supplementation, and cesarean section. Maintaining adequate nutrition and avoiding stress late in gestation may prevent the disease.

Anemia↗
PubMed1998

The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history.

Classical familial adenomatous polyposis (FAP) is a high-penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene. A variant of FAP is attenuated adenomatous polyposis coli, which results from germ-line mutations in the 5' and 3' regions of the APC gene. Attenuated adenomatous polyposis coli patients have "multiple" colorectal adenomas (typically fewer than 100) without the florid phenotype of classical FAP. Another group of patients with multiple adenomas has no mutations in the APC gene, and their phenotype probably results from variation at a locus, or loci, elsewhere in the genome. Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim. We have studied a set of 164 patients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants. Three patients with the I1307K allele were detected, each of Ashkenazi descent. Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unusually large number of metaplastic polyps of the colorectum. There is increasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma, but without the florid phenotype of classical FAP, and possibly with importance for colorectal cancer risk in the general population.

Adult↗
PubMed1998

A convenient method for affinity purification of maltose binding protein fusions.

Maltose binding protein of Escherichia coli is frequently employed as a fusion partner for the biosynthesis of polypeptides and proteins, largely because of the advantage provided by affinity purification of such a fusion. A mixture of cellulose and starch is shown to be a simple and effective alternative to the use of other, more complicated media which are often used for affinity chromatography of maltose binding protein fusions.

ATP-Binding Cassette Transporters↗
PubMed1998

Locus coeruleus neurons from morphine-treated rats do not show opiate-withdrawal hyperactivity in vitro.

In vitro studies have not consistently demonstrated naloxone-precipitated opiate-withdrawal hyperactivity of locus coeruleus neurons. The reason for this inconsistency may be because partial or complete withdrawal occurred during preparation of the locus coeruleus slice. The aim of the present study was to assay opiate withdrawal-related hyperactivity in neurons recorded from locus coeruleus slices while ensuring the maintenance of dependence until naloxone-precipitated withdrawal. Extracellular recordings were obtained from individual locus coeruleus neurons in slices from morphine-treated and drug-naive rats. Morphine 1 microM was present in all solutions during preparation and recording in slices from morphine-treated rats. The average firing rate of the drug-naive controls was 0.93 Hz (+/-0.04 Hz). Bath application of morphine (1 microM) almost completely suppressed firing in drug-naive controls (0.058 Hz, +/-0.04 Hz, n=12), whereas in solutions containing 1 microM morphine, the firing rate of cells from morphine-treated rats averaged 0.71 Hz (+/-0.05 Hz), indicating considerable, but incomplete tolerance. In the same slices, naloxone increased the average spontaneous firing of locus coeruleus cells to 0.96 Hz (+/-0. 04 Hz). Thus, naloxone did not produce withdrawal hyperactivity, but returned the cells from morphine-treated rats to control rates. We conclude that locus coeruleus cells in locus coeruleus slice preparations from morphine-treated rats did not demonstrate withdrawal-related hyperactivity even when dependence was maintained until naloxone-precipitated withdrawal. Thus, our results do not support a role for adaptations intrinsic to locus coeruleus neurons in withdrawal hyperexcitability, but instead imply the necessity of functional afferent activity.

Analysis of Variance↗
PubMed1998

The effect of reduction of door-to-needle times on the administration of thrombolytic therapy for acute myocardial infarction.

Optimal management of acute myocardial infarction requires rapid administration of thrombolytic therapy. However, only patients who fulfill the following specific criteria are likely to benefit from this treatment: admission within 12 hours of the onset of symptoms, no contraindications, ST elevation or possible new-onset left bundle branch block on the admission electrocardiogram. We employed an aggressive policy to reduce the delay between admission to hospital and the administration of thrombolysis (the 'door-to-needle time'), and investigated whether this approach affected the accuracy of administration of thrombolysis. Patients admitted to the cardiac care unit with acute myocardial infarction, or who were thrombolysed, were identified retrospectively over two equivalent 4-month periods before and after implementation of our policy. Patients were considered eligible for thrombolysis if they fulfilled the criteria mentioned above. The mean (SD) door-to-needle time for all patients who received thrombolysis on admission decreased from 61(70) to 19(20) minutes (p = 0.0004). The proportion of patients eligible for thrombolysis who received treatment increased from 24/38 to 30/30 (p = 0.0002). However, the proportion of patients receiving thrombolysis who did not fulfill our criteria also increased, from 3/27 to 11/41 (p = 0.1). There were no complications of thrombolysis in the first study period, but two cerebrovascular accidents in the second period; both patients fulfiled our criteria for treatment. We conclude that simple educational measures greatly reduced door-to-needle times and led to a higher proportion of eligible patients receiving thrombolysis. However, greater pressure on medical staff to make rapid management decisions increased the proportion of patients being thrombolysed inappropriately.

Aged↗
PubMed1997

Structure of crystal form IX of bovine pancreatic ribonuclease A.

The X-ray structure of crystal form IX of bovine pancre- atic ribonuclease A (space group P2(1)2(1)2(1)) is reported at 1.6 A resolution. The structure was refined to an R factor of 15.0% and includes coordinates for two sulfate ions, four methanol molecules and 82 waters. The structure could be superimposed on the highest resolution crystal structure of bovine pancreatic fibonuclease available (in space group P2(1)) with an r.m.s, difference in main-chain atomic positions of 0.51 A. Most of the larger differences between the two structures could be related to crystal lattice contacts. Superposition of the new structure with eight other structures of ribonuclease in six crystal forms resulted in an r.m.s, deviation from the average structure of 0.43 A for all main-chain atoms. This similarity among structures exists in spite of the fact that all nine molecules are in different crystal environments.

Journal Article↗
PubMed1997

Extent and nature of contacts between protein molecules in crystal lattices and between subunits of protein oligomers.

A survey was compiled of several characteristics of the intersubunit contacts in 58 oligomeric proteins, and of the intermolecular contracts in the lattice for 223 protein crystal structures. The total number of atoms in contact and the secondary structure elements involved are similar in the two types of interfaces. Crystal contact patches are frequently smaller than patches involved in oligomer interfaces. Crystal contacts result from more numerous interactions by polar residues, compared with a tendency toward nonpolar amino acids at oligomer interfaces. Arginine is the only amino acid prominent in both types of interfaces. Potentials of mean force for residue-residue contacts at both crystal and oligomer interfaces were derived from comparison of the number of observed residue-residue interactions with the number expected by mass action. They show that hydrophobic interactions at oligomer interfaces favor aromatic amino acids and methionine over aliphatic amino acids; and that crystal contacts form in such a way as to avoid inclusion of hydrophobic interactions. They also suggest that complex salt bridges with certain amino acid compositions might be important in oligomer formation. For a protein that is recalcitrant to crystallization, substitution of lysine residues with arginine or glutamine is a recommended strategy.

Crystallization↗