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Biomedical subjects

G Sutton

Publications and source records attributed to G Sutton.

At least 19 recordsLinked to original sources
PubMed1998

Guanylyltransferase and RNA 5'-triphosphatase activities of the purified expressed VP4 protein of bluetongue virus.

We have examined the RNA-capping enzyme activities of bluetongue virus (BTV) minor core protein, VP4. Recombinant BTV VP4 protein was purified to homogeneity from insect cell culture infected with a baculovirus VP4 of BTV serotype 10. We demonstrate that the purified protein, and VP4 encapsidated in core-like particles, react with GTP and covalently bind GMP via a phosphoamide linkage, a characteristic feature of guanylyltransferase enzyme. VP4 also catalyses a GTP-PPi exchange reaction indicating that the protein is the guanylyltransferase of the virus. In addition, VP4 possesses an RNA 5'-triphosphatase activity which catalyses the first step in the RNA-capping sequence. Further, an inorganic pyrophosphatase activity was identified which may aid the transcription activity within the virus by removing inorganic pyrophosphate which is an inhibitor of the polymerization reaction. Finally, the direct evidence of VP4 capping activity has been obtained by demonstrating in vitro transfer of GMP to the 5' end of in vitro synthesized BTV ssRNA transcripts to form a cap structure.

Acid Anhydride Hydrolases↗
PubMed1998

Phase 2 trial of single agent ifosfamide/mesna in patients with platinum/paclitaxel refractory ovarian cancer who have not previously been treated with an alkylating agent.

Ifosfamide has been shown to possess modest activity in patients with platinum/cyclophosphamide refractory ovarian cancer. Current standard initial chemotherapy for ovarian cancer does not include an alkylating agent (paclitaxel substituting for cyclophosphamide). To evaluate the activity of ifosfamide in patients with refractory ovarian cancer who had not previously received an alkylating agent, 21 patients with platinum/paclitaxel refractory disease were treated with the drug as a single agent (1.8 g/m2/day x 3 days, with treatment repeated every 28 days). Treatment was reasonably well tolerated in most patients, although 1 individual was removed from study secondary to neurotoxicity. One patient exhibited an objective response of measurable disease, while a second individual had a major decrease in CA-125 levels (no measurable disease present) following therapy. An additional patient experienced disappearance of severe pelvic pain following treatment but failed to meet the criteria for a partial response. We conclude that ifosfamide has modest activity in platinum/paclitaxel refractory ovarian cancer. However, the level of effectiveness does not appear to be increased in individuals who are alkylating-agent naive, compared to previously reported experience in patients with prior exposure to this class of cytotoxic drugs (10-15% response rate).

Adult↗
PubMed1998

New generation of African horse sickness virus vaccines based on structural and molecular studies of the virus particles.

African horse sickness virus (AHSV) is a member of the genus Orbivirus, which also includes bluetongue virus (BTV) and epizootic haemorrhagic disease (EHDV) virus. These orbiviruses have similar morphological and biochemical properties, with distinctive pathobiological properties and host ranges. Sequencing studies of the capsid proteins have revealed evolutionary relationships between these viruses. Biochemical studies of the viruses together with the expression of individual proteins and protein complexes have resulted in the development of new generation vaccines. Baculovirus expressed AHSV VP2 provides protection against death caused by AHSV challenge. Similarly, BTV VP2 alone elicits protective neutralising antibodies against BTV in sheep, which is enhanced in the presence of VP5. Recent developments in biotechnology (multiple gene expression baculovirus systems) have made it possible to synthesise orbivirus particles that biochemically and immunologically mimic authentic virions but lack the genetic material. Particle doses as low as 10 micrograms elicit responses that are sufficient to protect sheep 15 months post vaccination, against virulent virus challenge. Moreover, knowledge of the three dimensional structure of these particles enables us to engineer them to deliver multiple foreign peptide components representing other viral epitopes (e.g. foot and mouth disease virus and influenza virus) in order to elicit protective immunity.

African Horse Sickness Virus↗
PubMed1998

Paradoxical response to photorefractive treatment for postkeratoplasty astigmatism.

A 42-year-old woman with functionally disabling postkeratoplasty astigmatism in her right eye 3 years after corneal transplantation for keratoconus received photorefractive keratectomy for high astigmatism in that eye. This did not reduce her astigmatism. The procedure was repeated and corneal astigmatism paradoxically increased. The forces within the pseudo-optical ring that cause and maintain astigmatism in corneal transplants may be a significant factor in the unpredictable response of some corneal transplants to excimer photorefractive astigmatism correction.

Adult↗
PubMed1998

Long-term (5 year) effects of transient (silent) ischaemia on left ventricular systolic function in stable angina. Clinical and radionuclide study.

AIMS: (a) to assess short (1 year) and long-term (5 year) changes in left ventricular ejection fraction in patients with stable coronary disease with or without ECG evidence of transient ischaemia during daily life on routine therapy, and (b) to assess whether patients with recurrent transient ischaemic episodes have a particular propensity to gradual deterioration in left ventricular ejection fraction in the absence of infarction. METHODS AND RESULTS: One hundred and forty eight patients (127 males; mean age 59 years), part of a natural history cohort of 172 patients who had undergone exercise testing, 48 h ambulatory ST monitoring, and resting radionuclide ventriculography at baseline, and who had not suffered any intervening cardiac event, underwent repeat radionuclide ventriculography at 1 year follow-up on identical or very similar medications. Furthermore, 56 patients (50 males; mean age 65 years) of this cohort, who had ischaemia both on exercise testing and ambulatory monitoring at baseline (n=33), or no ischaemia on either test at baseline (n=23), and who had suffered no intervening event, underwent repeat exercise testing, ambulatory monitoring and radionuclide ventriculography at a mean of 61.8 months follow-up. In 38 of these 56 cases, long-term testing mirrored baseline testing in terms of presence or absence of ischaemia (both tests +, n=25; both tests -, n=13). At one year there was no change in left ventricular ejection fraction, either for the whole group (n=148; left ventricular ejection fraction 47=11.6% - 47.13+11.07%, P=ns) or for subgroups with (n=62; left ventricular ejection fraction 48+12.1%-48.5+10.5%, P=ns) and without (n=86; left ventricular ejection fraction 46.2+10.4%-46.2+11.3%, P=ns) evidence of transient ischaemia at baseline. At 61 months, there was a small fall in mean left ventricular ejection fraction for the total study group (n=56; left ventricular ejection fraction 45.8+9.3%-42.1+8.8%, P<0.05); however, this fall was not significant for those patients with both baseline and 5 year evidence of transient ischaemia (n=25; left ventricular ejection fraction 44.9+8.7%-41.3+7.5%, P=0.056). CONCLUSION: In medically treated stable coronary patients who do not suffer any intervening cardiac event, recurrent transient (silent) ischaemic episodes do not, in themselves, lead to gradual deterioration in left ventricular systolic function over a 1-5 year period.

Adult↗
PubMed1997

Effects of domain-switching and site-directed mutagenesis on the properties and functions of the VP7 proteins of two orbiviruses.

Based on the crystal structure of the VP7 major core protein of bluetongue virus serotype 10 (BTV-10) and that of the top domain of the VP7 protein of African horsesickness virus serotype 4 (AHSV-4), chimeras and site-directed mutants of the proteins were constructed and the products analyzed with respect to their properties and functions. Chimeras with the central upper domain of BTV-10 VP7 replaced by that of AHSV-4 VP7 (construct BAB) formed trimers, as did the converse construct (ABA). Further, both proteins exhibited the expected conformational epitopes of the constituent sequences. Using BAB VP7 it was demonstrated that residues of the upper domain of AHSV-4 VP7 contribute to the observed insolubility of the protein. By contrast, ABA VP7 protein was as soluble as wild-type BTV-10 VP7. Replacement of selected amino acid residues in the top domain (e.g., A167 by R; F209 by T) improved the solubility of BAB VP7. Since the trimeric BAB and ABA VP7 proteins did not form core-like particles (CLPs) when coexpressed with BTV VP3, it was concluded that trimerization of chimeric VP7 is not sufficient for CLP formation. When the N-terminal region of the ABA protein (aa 1-120) was replaced by the respective sequences of BTV VP7 (construct BBA), the protein aggregated and did not form CLPs with coexpressed BTV VP3, most likely due to disruption of the required contacts between the N- and C-terminal regions of the bottom domain, leading to incorrect folding of the chimera.

Amino Acid Substitution↗
PubMed1997

Chronic ethanol increases N-methyl-D-aspartate-stimulated nitric oxide formation but not receptor density in cultured cortical neurons.

The effects of prolonged ethanol exposure on excitatory amino acid receptor stimulated nitric oxide (NO) formation were examined in primary rat cortical neuronal cultures. Chronic ethanol (4 days, 100 mM) potentiated N-methyl-D-aspartate (NMDA)-stimulated NO formation as determined by measuring the conversion of [3H]arginine to [3H]citrulline. In contrast, chronic ethanol had no effect on NO formation stimulated by kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxalonepropionic acid, or the calcium ionophore ionomycin. Potassium chloride-stimulated NO formation was also enhanced by chronic ethanol treatment, but this effect was not seen in the presence of the ionotropic glutamate receptor antagonists MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione. Immunoblot analysis of expression of NR1, NR2A, and NR2B receptor subunits showed no difference between control and chronic ethanol-treated cultures. In support of this apparent lack of change in receptor density, there was no difference in the specific binding of 125I-MK-801 between control and chronic ethanol-treated groups. These results demonstrate that prolonged ethanol exposure selectively enhanced NMDA receptor-stimulated NO formation, which may play an important role in alcohol dependence, withdrawal, and alcohol-associated brain damage. These results also suggest that chronic ethanol-induced increases in NMDA receptor function may not be due to a simple increase in the number of NMDA receptors or change in NMDA receptor subunit composition but may instead reflect more complicated and subtle changes.

Animals↗
PubMed1997

Bluetongue virus VP6 protein binds ATP and exhibits an RNA-dependent ATPase function and a helicase activity that catalyze the unwinding of double-stranded RNA substrates.

RNA-dependent ATPase and helicase activities have been identified associated with the purified VP6 protein of bluetongue virus, a member of the Orbivirus genus of double-stranded RNA (dsRNA; Reoviridae family) viruses. In addition, the protein has an ATP binding activity. RNA unwinding of duplexes occurred with both 3' and 5' overhang templates, as well as with blunt-ended dsRNA, an activity not previously identified in other viral helicases. Although little sequence similarity to other helicases was detected, certain similarities to motifs commonly attributed to such proteins were identified.

Adenosine Triphosphatases↗
PubMed1996

Tenuous link between ischaemic threshold and both ambulatory ischaemia and symptom status over time in stable angina: a 5-year follow-up study.

This study evaluates changes in ischaemic threshold over a 5-year period in patients with stable angina pectoris, who did not suffer any intervening cardiac event. Changes in ischaemic threshold are related to alterations in symptomatic status and ambulatory ischaemia. Over long-term follow-up, there is a significant fall in ischaemic threshold in such patients (mean heart rate at onset of ischaemia fell from 104 +/- 17.8 to 97 +/- 17.4 bpm: P < 0.001), but this is not matched by a worsening of either symptoms or ischaemia during daily life. In the 68% of patients that had a reduction in ischaemic threshold of > or = 5 bpm, 68% had either definite reduction or no change in symptoms and 84% had either reduction, abolition or no change in transient ischaemic activity. The dissociation between ischaemic threshold, ambulatory ischaemia and symptoms has implications for long-term monitoring and management of the patient with stable angina.

Adult↗
PubMed1996

Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study.

This is a Phase II groupwide study of the Gynecologic Oncology Group (GOG) to determine the toxicity and efficacy of a combination of ifosfamide and doxorubicin in patients with advanced or metastatic leiomyosarcomas of the uterus who had not received other chemotherapy. Thirty-five women were entered into this study; 1 patient was ineligible (primary not documented), leaving 34 patients treated with ifosfamide, 5.0 g/m2/24 hr, and mesna, 6.0 g/m2/36 hr, by continuous IV infusion preceded by doxorubicin, 50 mg/m2 iv over 15 min. Each course of therapy was repeated every 3 weeks if counts allowed. One patient was inevaluable for response, leaving 34 evaluable for toxicity and 33 evaluable for response of chemotherapy. GOG grade 3 or 4 granulocytopenia occurred in 17 patients (48.6%), 2 patients developed granulocytopenic fever (5.7%), and 1 died of sepsis. Two patients developed grade 3 thrombocytopenia, and 1 died of cardiotoxicity. There were nine partial and one complete responses for an overall response rate of 30.3%; the response duration averaged 4 months. The combination of ifosfamide and doxorubicin is toxic but has moderate activity in patients with advanced or metastatic leiomyosarcoma of the uterus.

Adult↗
PubMed1996

Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group.

OBJECTIVE: To determine the effectiveness and toxicity of ifosfamide chemotherapy in women with metastatic or recurrent endometrial stromal sarcomas unexposed to other chemotherapy. METHODS: In a prospective, multi-institutional phase II study conducted by the Gynecology Oncology Group, the starting dose of ifosfamide was 1.5 g/m2 given daily intravenously (i.v.) for 5 days (reduced to 1.2 g/m2 daily in patients who had previously received radiotherapy). Mesna (2 mercaptoethane sodium sulfonate) was given i.v. immediately and at 4 and 8 hours after the administration of ifosfamide. Each dose of mesna was 20% of the total daily dose of ifosfamide. Patients were treated every 3 weeks if blood counts permitted. Therapy was discontinued if there was progression of the cancer or unacceptable toxicity. RESULTS: Twenty-two patients were entered into this study. One was excluded from analysis because of the wrong histologic type, leaving 21 evaluable for response and toxicity. Gynecologic Oncology Group grade 3 or 4 granulocytopenia occurred in four patients (19%), and one patient each experienced Gynecologic Oncology Group grade 4 anemia and genitourinary toxicity. Three patients experienced complete tumor responses and four had partial responses, for an overall response rate of 33.3%. CONCLUSION: Ifosfamide is active in the therapy of women with chemotherapy-naive metastatic or recurrent endometrial stromal sarcomas.

Antineoplastic Agents, Alkylating↗
PubMed1996

The construction of Arabidopsis expressed sequence tag assemblies. A new resource to facilitate gene identification.

The generation of large numbers of partial cDNA sequences, or expressed sequence tags (ESTs), has provided a method with which to sample a large number of genes from an organism. More than 25,000 Arabidopsis thaliana ESTs have been deposited in public databases, producing the largest collection of ESTs for any plant species. We describe here the application of a method of reducing redundancy and increasing information content in this collection by grouping overlapping ESTs representing the same gene into a "contig" or assembly. The increased information content of these assemblies allows more putative identifications to be assigned based on the results of similarity searches with nucleotide and protein databases. The results of this analysis indicate that sequence information is available for approximately 12,600 nonoverlapping ESTs from Arabidopsis. Comparison of the assemblies with 953 Arabidopsis coding sequences indicates that up to 57% of all Arabidopsis genes are represented by an EST. Clustering analysis of these sequences suggests that between 300 and 700 gene families are represented by between 700 and 2000 sequences in the EST database. A database of the assembled sequences, their putative identifications, and cellular roles is available through the World Wide Web.

Arabidopsis↗
PubMed1995

The minimal gene complement of Mycoplasma genitalium.

The complete nucleotide sequence (580,070 base pairs) of the Mycoplasma genitalium genome, the smallest known genome of any free-living organism, has been determined by whole-genome random sequencing and assembly. A total of only 470 predicted coding regions were identified that include genes required for DNA replication, transcription and translation, DNA repair, cellular transport, and energy metabolism. Comparison of this genome to that of Haemophilus influenzae suggests that differences in genome content are reflected as profound differences in physiology and metabolic capacity between these two organisms.

Antigenic Variation↗
PubMed1995

Malignant degeneration of a mature cystic teratoma five decades after discovery.

Malignant degeneration of mature cystic teratomas has been reported in 1-3% of cases. A patient with the unusual occurrence of a stage IIIC squamous cell carcinoma arising in a mature teratoma over 50 years after initial diagnosis is presented. The patient was treated with pelvic radiotherapy. The role of serum squamous cell carcinoma antigen in detecting degeneration of mature cystic teratomas at an early stage is considered.

Aged↗
PubMed1995

Retroperitoneal leiomyosarcoma: eight cases and a literature review.

Leiomyosarcoma, a rare malignancy of smooth muscle, may arise from the retroperitoneum and present with the same vague symptoms as a malignancy of the pelvic organs. The purpose of this paper is to review eight cases of retroperitoneal leiomyosarcoma and to illustrate the presenting symptoms, prognostic indicators, and outcomes of patients seen at Indiana University Medical Center between 1989 and 1994. Patients in this study were white females who presented between the ages of 46 and 73 (mean age of 61.4) with nonspecific presenting symptoms of weight loss and back pain (37.5% for each). Tumor size (mean diameter of 14.6 cm in the range 4 to 35 cm), tumor extension, and the presence of distant metastases were of greater prognostic significance than tumor grade (7/8 were grade II, 1/8 was grade I). Surgical resection improved long-term prognosis; three of five patients undergoing resection are alive with no evidence of disease compared to zero of three treated nonsurgically. Due to location and vague presenting symptoms, this tumor continues to have a bleak prognosis and further evaluation and innovative treatment are required before a reasonable cure rate may be expected.

Aged↗
PubMed1995

Detection of ambulatory ischaemia is not of practical clinical value in the routine management of patients with stable angina. A long-term follow-up study.

It has been reported that medically treated patients with stable angina and positive exercise test for ischaemia have an adverse 1-2 year outlook if they are shown also to have transient, and predominantly silent, ischaemic episodes detected by ambulatory ST segment monitoring during their daily activities: it has been suggested that this investigation could be used to identify patients more likely to benefit from early investigation and treatment. We assessed the long-term (up to 65 months) prognostic significance of transient ischaemic episodes during daily activities in 172 patients routinely attending cardiac outpatients with medically treated stable angina who had undergone exercise testing and 48 h of ambulatory ST segment monitoring between February 1988 and August 1989 for this purpose. A positive exercise test for ischaemia was not a prerequisite for inclusion. One hundred and four patients (60.5%) had a positive exercise test for ischaemia and 72 (42%) had transient ischaemia during daily activities (63 had both tests positive). Over a median 50-month follow-up period 54 patients suffered at least one cardiac event (primary event: cardiac death n = 7; non-fatal myocardial infarction n = 11; unstable angina n = 18; elective CABG/PTCA n = 18). Two further patients suffered non-cardiac death. Cardiac events, either objective (cardiac death or non-fatal myocardial infarction) or subjective (unstable angina or revascularisation) were no more likely to occur in those with transient ischaemia during daily life when compared with those without, at follow-up times up to 65 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Intraspecific variation in small-subunit rRNA sequences in GenBank: why single sequences may not adequately represent prokaryotic taxa.

Small-subunit rRNA (SSU rRNA) sequencing is a powerful tool to detect, identify, and classify prokaryotic organisms, and there is currently an explosion of SSU rRNA sequencing in the microbiology community. We report unexpectedly high levels of intraspecific variation (within and between strains) of prokaryote SSU rRNA sequences deposited in GenBank. A total of 82% of the prokaryote species with two published SSU rRNA sequences had more variable positions than a 0.1% random sequencing error would predict, and 48% of these sequence pairs had more variable positions than predicted by a 1.0% random sequencing error. Other sources of sequence variability must account for some of this intraspecific variation. Given these results, phylogenetic studies and biodiversity estimates obtained by using prokaryotic SSU rRNA sequences cannot proceed under the assumption that rRNA sequences of single operons from single isolates adequately represent their taxa. Sequencing SSU rRNA molecules from multiple operons and multiple isolates is highly recommended to obtain meaningful phylogenetic hypotheses, as is careful attention to accurate strain identification.

Bacteria↗