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Biomedical subjects

G Wilson

Publications and source records attributed to G Wilson.

At least 73 records · Page 4Linked to original sources
PubMed1999

Hormonal treatment after cytotoxic therapy stimulates recovery of spermatogenesis.

Previous studies have shown that treatment of rats with gonadotropin-releasing hormone (GnRH) analogues or steroids either before exposure to procarbazine or radiation or after irradiation enhances subsequent levels of spermatogenesis. We demonstrate here that giving a GnRH agonist after procarbazine injection also enhances spermatogenesis and fertility. We also demonstrate that GnRH agonist stimulated recovery of spermatogenesis and fertility not only when the hormone was administered immediately after irradiation, but also at 20 weeks after irradiation, after the decline in spermatogenesis had occurred. These results suggest that GnRH agonist treatment given to azoospermic men after cytotoxic therapy for cancer may stimulate the recovery of spermatogenesis and fertility.

Animals↗
PubMed1999

Identification of amino acid residues critical for aggregation of human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES. Characterization of active disaggregated chemokine variants.

Human CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation normal T cell expressed) self-associate to form high-molecular mass aggregates. To explore the biological significance of chemokine aggregation, nonaggregating variants were sought. The phenotypes of 105 hMIP-1alpha variants generated by systematic mutagenesis and expression in yeast were determined. hMIP-1alpha residues Asp26 and Glu66 were critical to the self-association process. Substitution at either residue resulted in the formation of essentially homogenous tetramers at 0.5 mg/ml. Substitution of identical or analogous residues in homologous positions in both hMIP-1beta and RANTES demonstrated that they were also critical to aggregation. Our analysis suggests that a single charged residue at either position 26 or 66 is insufficient to support extensive aggregation and that two charged residues must be present. Solution of the three-dimensional NMR structure of hMIP-1alpha has enabled comparison of these residues in hMIP-1beta and RANTES. Aggregated and disaggregated forms of hMIP-1alpha, hMIP-1beta, and RANTES generally have equivalent G-protein-coupled receptor-mediated biological potencies. We have therefore generated novel reagents to evaluate the role of hMIP-1alpha, hMIP-1beta, and RANTES aggregation in vitro and in vivo. The disaggregated chemokines retained their human immunodeficiency virus (HIV) inhibitory activities. Surprisingly, high concentrations of RANTES, but not disaggregated RANTES variants, enhanced infection of cells by both M- and T-tropic HIV isolates/strains. This observation has important implications for potential therapeutic uses of chemokines implying that disaggregated forms may be necessary for safe clinical investigation.

Amino Acid Sequence↗
PubMed1999

Effects of reactive oxygen species on myofilament function in a rabbit coronary artery ligation model of heart failure.

This study aimed to determine structural alterations occurring in cardiac myofilaments after exogenous application of oxidants and the effects of oxidants on contractile protein function in a rabbit coronary artery ligation model of heart failure. Myocardial "stiffness" was higher in the ligated animals (Lig) than sham-operated controls (Sh, 4.9+/-1.5 versus 1.6+/-0.8 mN.mm-1). Superoxide anion (O2-) exposure decreased active stiffness in both groups, whereas hypochlorous acid (HOCl) had no effect in Lig but increased stiffness in Sh. Resting stiffness was higher in Lig than Sh (0.6+/-0.2 versus 0.2+/-0.1 mN.mm-1), remaining unchanged after O2- exposure but increasing after HOCl in both groups. The frequency at minimum stiffness was lower in Lig than Sh (0.9+/-0.2 versus 1. 7+/-0.6 Hz) and was reduced in both groups after oxidant exposure. Myofilament calcium sensitivity (pCa50) was not altered by O2- in Sh but increased in Lig (pCa50 increased from 5.41+/-0.05 to 5.56+/-0. 06). Protease contamination in the xanthine oxidase used to generate O2- did not affect myofilament ultrastructure at the concentrations used here. These data demonstrate that contractile proteins from "failed" myocardium have a similar response to exogenously applied oxidants as controls and that application of protease-contaminated xanthine oxidase system does not degrade the contractile protein structure.

Actin Cytoskeleton↗
PubMed1999

Soy allergy in infants and children with IgE-associated cow's milk allergy.

OBJECTIVES: To determine the prevalence of soy allergy in IgE-associated cow's milk allergy (CMA). STUDY DESIGN: Children <3.5 years with documented IgE-associated CMA (n = 93) were evaluated for soy allergy by double-blind, placebo-controlled food challenge, open challenge, or convincing previous history of an anaphylactic reaction to soy. Children tolerant to soy at entry received soy formula and were followed up for 1 year. RESULTS: Of this IgE-associated CMA cohort (ages 3 to 41 months), 14% (95% CI = 7. 7%-22.7%) were determined to have soy allergy, 12 definitely at entry and 1 possibly after 1 year of soy ingestion. The latter child experienced severe failure to thrive at enrollment and exhibited improved growth while receiving soy during follow-up but was diagnosed with eosinophilic esophagitis at study completion. Improved growth (P <.05) occurred in the non-soy-allergic cohort ingesting soy formula (579 31 mL/d) during the year of follow-up. CONCLUSIONS: Soy allergy occurs in only a small minority of young children with IgE-associated CMA. As such, soy formula may provide a safe and growth-promoting alternative for the majority of children with IgE-associated CMA shown to be soy tolerant at the time of introduction of soy formula.

Child, Preschool↗
PubMed1999

Metabolic adaptations to a high-fat diet in endurance cyclists.

We examined the time course of metabolic adaptations to 15 days of a high-fat diet (HFD). Sixteen endurance-trained cyclists were assigned randomly to a control (CON) group, who consumed their habitual diet (30% +/- 8% mJ fat), or a HFD group, who consumed a high-fat isocaloric diet (69% +/- 1% mJ fat). At 5-day intervals, the subjects underwent an oral glucose tolerance test (OGTT); on the next day, they performed a 2.5-hour constant-load ride at 70% peak oxygen consumption (VO2peak), followed by a simulated 40-km cycling time-trial while ingesting a 10% 14C-glucose + 3.44% medium-chain triglyceride (MCT) emulsion at a rate of 600 mL/h. In the OGTT, plasma glucose concentrations at 30 minutes increased significantly after 5 days of the HFD and remained elevated at days 10 and 15 versus the levels measured prior to the HFD (P < .05). The activity of carnitine acyltransferase (CAT) in biopsies of the vastus lateralis muscle also increased from 0.45 to 0.54 micromol/g/min over days 0 to 10 of the HFD (P < .01) without any change in citrate synthase (CS) or 3-hydroxyacyl-coenzyme A dehydrogenase (3-HAD) activities. Changes in glucose tolerance and CAT activity were associated with a shift from carbohydrate (CHO) to fat oxidation during exercise (P < .001), which occurred within 5 to 10 days of the HFD. During the constant-load ride, the calculated oxidation of muscle glycogen was reduced from 1.5 to 1.0 g/min (P < .001) after 15 days of the HFD. Ingestion of a HFD for as little as 5 to 10 days significantly altered substrate utilization during submaximal exercise but did not attenuate the 40-km time-trial performance.

Adaptation, Physiological↗
PubMed1999

HPMA copolymer platinates as novel antitumour agents: in vitro properties, pharmacokinetics and antitumour activity in vivo.

The aim of this study was to compare in vitro and in vivo HPMA copolymer platinates with cisplatin in terms of platinum release, toxicity and antitumour activity. N-(2-hydroxypropyl)methacrylamide (HPMA) conjugates containing peptidyl side-chains (Gly-Gly or Gly-Phe-Leu-Gly) terminating in either carboxylate or amino species were prepared. The carboxylate polymeric intermediate was reacted with cisplatin, and the polymeric diamine with potassium tetrachloroplatinate to produce HPMA copolymer platinates of Mw 25,000-31,000 Daltons with a platinum loading of 3-7 wt%. The diglycyl spacer was selected because it is non-biodegradable, whereas the tetrapeptide spacer is known to be cleaved by the lysosomal thiol-dependent proteases. In vitro the HPMA copolymer platinates displayed a range of platinum release rates at pH 7.4 and 5.5; from < 5%/24 h in the case of the diamino species which require enzymatic activation, to > 80%/24 h in the case of the carboxylate. Cisplatin and the fast releasing carboxylate species displayed IC50 values of 10 micrograms/ml Pt-equivalent against B16F10 cells in vitro, whereas the slow releasing conjugates were not cytotoxic over the dose range studied. Antitumour activity of HPMA copolymer platinates was first evaluated against L1210 and B16F10 tumours inoculated intraperitoneally (i.p.). When conjugates were administered i.p., the antitumour activity observed against L1210 tumours was within the range seen for free cisplatin (ratio of mean survival of treated animals to mean survival of controls, T/C, 1.20-1.70). Neither cisplatin nor HPMA copolymer platinates were active against intraperitoneal (i.p.) B16F10 tumours when administered i.p. However, when conjugates were administered intravenously (i.v.) to treat subcutaneous (s.c.) B16F10 tumours grown to palpable size, free cisplatin was still not active but the HPMA copolymer platinates bearing carboxylate and diamine platinates showed significant antitumour activity (T/C > 1.35). Throughout these studies, the polymer platinates were 5-15-fold less toxic than cisplatin in vivo. After i.v. administration, the blood clearance of HPMA copolymer platinate was considerably slower (t1/2 alpha approximately 10 h) than seen for free cisplatin (t1/2 alpha < 5 min). HPMA copolymer platinates (15 mg/kg Pt-equivalent) gave rise to an approximately 60-fold increase in Pt AUC in B16F10 tumour tissue than was achieved after administration of cisplatin at its maximum tolerated dose (MTD) (1 mg/kg).

Animals↗
PubMed1999

Epirubicin, cisplatin and oral UFT with leucovorin ('ECU'): a phase I-II study in patients with advanced upper gastrointestinal tract cancer.

BACKGROUND: ECF (epirubicin, cisplatin, protracted venous fluorouracil) is superior to FAMTX in gastroesophageal cancer, but protracted fluorouracil adds to its morbidity and cost. In this dose-escalation pilot study, fluorouracil was replaced by oral UFT and leucovorin. PATIENTS AND METHODS: Thirty unpretreated patients with advanced upper gastrointestinal cancers received epirubicin 50 mg/m2 and cisplatin 60 mg/m2 i.v. on day 1, and leucovorin 45 mg p.o. on days 1, 8 and 15, of a 21-day cycle for up to 8 cycles. UFT was taken 12-hourly throughout, at escalating doses in four cohorts ranging from 150-325 mg/m2 per day. RESULTS: The maximum tolerable dose of UFT, recommended for further study, was 200 mg/m2 per day. At higher doses, more than two-thirds patients required dose reductions, although mostly for persistent mild (CTC grade 2) nausea, diarrhoea or fatigue, rather than for severe acute toxicity. Myelotoxicity was mild. Twenty patients, including 15 with gastroesophageal cancer, had assessable disease. Among these there were nine WHO objective responses, all in gastroesophageal patients, including two radiological complete responses. CONCLUSIONS: ECU is well tolerated at the defined dose, with activity comparable to ECF in gastroesophageal cancer. UFT and other oral 5FU dosing strategies make promising components of combination chemotherapy, deserving further, randomised evaluation.

Administration, Oral↗
PubMed1999

c-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia.

Genomic DNA from 60 cases of acute myeloid leukaemia (AML) was screened for mutations in the c-kit gene. DNA from all 21 exons was subjected to polymerase chain reaction (PCR) amplification and analysis by conformation sensitive gel electrophoresis (CSGE); exons showing altered CSGE patterns were then sequenced. Mutations were identified only in those patients with inv(16) (3/7 cases) or t(8;21) (1/2 cases) and comprised three in-frame deletion plus insertion mutations (exon 8) and one point mutation (exon 10, GTA --> ATA, Val530Ile). Exons 8 and 10 were then analysed in 31 further cases of inv(16) (n = 14) and t(8;21) (n = 17), revealing four additional exon 8 in-frame deletion plus insertion mutations, all of which were in cases of inv(16). All exon 8 in-frame deletion plus insertion mutations (n = 7) involved the loss or replacement of the codon for Asp419 which is highly conserved cross species and is located in the receptor's extracellular domain. The high frequency of the c-kit proto-oncogene exon 8 deletion plus insertion mutations in AML suggests an essential role for this region of the receptor's extracellular domain. The association with inv(16) invites speculation as to the link between these two changes in the pathogenesis of AML.

Acute Disease↗
PubMed1999

Timing of apical closure of the maxillary canine and mandibular first molar teeth of cats.

Stage of apical closure was determined by radiographing the jaws of 15 cats at intervals from 5-11 months of age. The apices of the left mandibular first molar tooth were closed in all 15 cats by seven months of age and the apices of the left maxillary canine teeth were all closed by 11 months of age. The implications of the age of closure on endodontic pathology and treatment are discussed.

Animals↗
PubMed1999

Hormone pretreatment enhances recovery of spermatogenesis in rats after neutron irradiation.

Previous studies showed that a 6-week pretreatment of rats with testosterone plus estradiol enhanced the recovery of spermatogenesis 9 weeks after gamma irradiation, resulting in a dose-modifying factor (DMF) of about 2. To test whether the effect of the hormone treatment was mediated through changes in oxygen tension, thiol levels or DNA repair, we irradiated the testes of rats with neutrons, which depend less on these factors than does low-LET radiation for their cytotoxic action. Control rats and rats treated with testosterone plus estradiol were irradiated with 0.7-2.7 Gy of cyclotron-generated high-energy neutrons. The recovery of spermatogenesis was assessed 9 weeks after irradiation by testis weights, sperm counts and the tubule repopulation indices. Greater recovery of spermatogenesis was observed for all end points, with a DMF of about 2 for rats treated with testosterone plus estradiol compared to the irradiated, cholesterol-treated rats. The equal protection factors for neutrons and gamma rays indicate that oxygen, thiols and repair of DNA damage are unlikely to be involved in the protective effect of the hormone treatment.

Animals↗
PubMed1999

Relationship between strength qualities and performance in standing and run-up vertical jumps.

BACKGROUND: The purpose of this investigation was to determine the relationships between the strength qualities of the leg extensor musculature and performance in vertical jumps (VJ) performed from a standing position and a run-up. METHODS: Twenty-nine males with experience in jumping activities were tested for vertical jumping capacities with a standing VJ (double leg takeoff) and run-up jumps from a 1, 3, 5 and 7 stride approach (single leg takeoff). The speed-strength and maximum strength qualities of the leg extensors were assessed by tests involving concentric, stretch-shortening cycle (SSC) and isometric muscular actions. Pearson's correlations and stepwise multiple regression was performed to describe the relationships with jumping performance. RESULTS: The speed-strength tests correlated significantly with both jump types (r = 0.55-0.82), but maximum strength did not. A drop jump test considered to measure reactive strength correlated more strongly with the run-up jump than the standing VJ. The standing VJ was best predicted by a low stretch load SSC test, whereas the run-up jump was best predicted by a model that also including the test of reactive strength. CONCLUSION: The role of maximum strength in jumping performance was not clear but speed-strength qualities were considered important. It was concluded that reactive strength is relatively more important for jumping from a run-up than for the standing VJ, and this should be reflected by appropriate training methods and test protocols for the assessment of athletes who jump.

Adult↗
PubMed1998

Late relapsing childhood lymphoblastic leukemia.

Childhood lymphoblastic leukemia (ALL) is usually assumed to have been permanently eradicated in patients in long-term remission, but occasionally can recur after many years. To learn more about the problem, we studied a group of children whose leukemia had been in remission for 10 or more years before relapse and tried to determine whether they had true recurrences or second malignancies. We studied children treated on Medical Research Council ALL protocols between 1970 and 1984 and followed up by the Clinical Trial Service Unit in Oxford. Detailed clinical and laboratory data was collected from the centers concerned on all who were reported to have had a recurrence of their leukemia after 10 or more years from the time of achieving first complete remission (CR1). To prove that the relapse was a true recurrence rather than a second or secondary leukemia, DNA extracted from archived marrow smears was subjected to polymerase chain reaction (PCR) analysis for the presence of an identical Ig heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement at initial diagnosis and subsequent relapse. A total of 1,134 of 2,746 children had survived 10 years or more (range, 10 to 24 years) in CR1 and of those, 12 (approximately 1%) had subsequently relapsed. Relapse blast cells were shown to express the common ALL antigen (CD 10) in all cases and an identical clonal IgH or TCR gene rearrangement was found on PCR analysis of DNA from diagnosis and relapse in all eight cases where DNA extraction was successful. A further program of therapy was successful in inducing a second CR in all patients, four of whom have succumbed to a second relapse after 12 to 27 months. The remaining eight are in continuing CR2 at a follow-up of 12 to 108 months (median, 52) from relapse. Although the risk of relapse of childhood ALL after 10 years in remission appears to be small (around 1%), it persists. This raises questions about how blasts can survive quiescent for so long and when we can truly be confident of cure, if ever.

Adult↗
PubMed1998

Crystal structure of restriction endonuclease BglI bound to its interrupted DNA recognition sequence.

The crystal structure of the type II restriction endonuclease BglI bound to DNA containing its specific recognition sequence has been determined at 2.2 A resolution. This is the first structure of a restriction endonuclease that recognizes and cleaves an interrupted DNA sequence, producing 3' overhanging ends. BglI is a homodimer that binds its specific DNA sequence with the minor groove facing the protein. Parts of the enzyme reach into both the major and minor grooves to contact the edges of the bases within the recognition half-sites. The arrangement of active site residues is strikingly similar to other restriction endonucleases, but the co-ordination of two calcium ions at the active site gives new insight into the catalytic mechanism. Surprisingly, the core of a BglI subunit displays a striking similarity to subunits of EcoRV and PvuII, but the dimer structure is dramatically different. The BglI-DNA complex demonstrates, for the first time, that a conserved subunit fold can dimerize in more than one way, resulting in different DNA cleavage patterns.

Bacillus↗
PubMed1998

A synthetic mimic of the secretory granule for drug delivery.

Secretory cells contain submicroscopic granules composed of a polyanionic polymer network that is collapsed owing to the presence of hydronium ions and weak base cations. The network is encapsulated within a lipid membrane, and functions as a vehicle for the osmotically inert storage of a variety of granule-bound endogenous mediator species, such as histamine, serotonin and proteases. These species are excreted from the granule and thence from the cell in response to external biochemical signals. Hydrogels that swell and shrink in response to external stimuli might serve as synthetic analogues of secretory granules. Here we describe the systematic engineering of multi-component, environmentally responsive hydrogel microspheres, coated with a lipid bilayer to mimic more closely the natural secretory granule. These microspheres exhibit pH- and ion-dependent volume phase transitions and ion-sensitive exchange of bound cations when the encapsulating lipid membrane is porated. We stimulated poration electrically in individual microgel particles immobilized and manipulated with a micropipette. This system could find use for the triggered release of encapsulated drugs in the body.

Acrylamides↗