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H Thomas

Publications and source records attributed to H Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2002

Rare variants identified in the HNF- 4 alpha beta-cell-specific promoter and alternative exon 1 lack biological significance in maturity onset diabetes of the young and young onset Type II diabetes.

AIMS/HYPOTHESIS: The recently identified alternative promoter (P2) of HNF-4 alpha is the major HNF-4 alpha transcription start site in pancreatic beta cells. The significance of the P2 promoter was shown by the identification of a mutation in the IPF-1 binding site of the alternative promoter which cosegregated with diabetes in a large MODY family. The role of the P2 promoter and the associated alternative exon 1 in both MODY and polygenic Type II (non-insulin-dependent) diabetes mellitus is not known. Linkage to this region in studies of Type II diabetes makes the P2 region a strong candidate for a role in Type II diabetes susceptibility. METHODS: To assess the role of the P2 region we screened MODY, young-onset Type II diabetic subjects, and probands from Type II diabetes families linked to chromosome 20 for variants of the P2 promoter and associated exon of HNF-4 alpha. RESULTS: Two variants were found that were not present in the control subjects. The -79 C/T substitution was present in a MODY family but did not perfectly cosegregate with diabetes. A -276 G/T substitution was identified in two UK young-onset diabetes probands but did not co-segregate with diabetes. Reporter gene studies did not indicate changes in transcriptional activity caused by either the -79 C/T or -276 G/T single nucleotide substitutions. CONCLUSION/INTERPRETATION: We found no evidence to suggest that variation in the P2 proximal promoter region and associated alternative exon 1 of HNF-4 alpha contribute to young onset Type II diabetes susceptibility in Northern Europeans.

Adolescent↗
PubMed2002

A phase II trial of ZD0473 in platinum-pretreated ovarian cancer.

The primary aim of this phase II trial was to assess the antitumour activity of ZD0473 in ovarian cancer patients who had failed initial platinum-based therapy. Patients (n=94) were classified as either platinum-sensitive (n=35) or platinum-resistant (n=59) depending on whether they had relapsed or progressed within 26 weeks of completing first-line platinum-based chemotherapy. Patients initially received 120 mg/m(2) ZD0473 as a 1-h intravenous (i.v.) infusion on day 1 of a 3-week cycle. If well tolerated, the dose could be escalated to 150 mg/m(2). Few patients (9%) withdrew because of treatment-related adverse events and no clinically significant oto-, nephro- or neurotoxicity was observed. Objective response rates for platinum-resistant and sensitive patients were 8.3 and 32.4%, respectively, and clinical benefit was observed in 76.5% of the sensitive patients. Median time to progression was 57 and 180 days, and median time to death was 242 and 402 days, for resistant and sensitive patients, respectively. In conclusion, ZD0473 has a manageable toxicity profile and encouraging activity in platinum-sensitive ovarian cancer patients.

Adult↗
PubMed2002

Results of ZD0473 in platinum-pretreated ovarian cancer: analysis according to platinum free interval.

Resistance to platinum-containing regimens can develop in many women with ovarian cancer and may lead to relapse in > 80% of patients. ZD0473 is a new-generation platinum agent that, in preclinical studies, shows evidence of antitumour activity and overcomes platinum-resistance mechanisms. This Phase II trial has evaluated the efficacy and tolerability of ZD0473 in second-line ovarian cancer patients. Patients received ZD0473 120 mg/m2 (1-h iv infusion, day 1 q 3-weeks); the starting dose was increased to 150 mg/m2 after a safety review. We report here on results when patients are divided into four cohorts depending upon whether they were considered platinum-resistant or -sensitive. Patients were placed into one of 3 cohorts if they were platinum resistant (relapsed/progressed < or = 26 weeks after completion of prior platinum-based chemotherapy) or cohort 4 if this period was > 26 weeks (sensitive). Ninety-four patients were recruited to the trial (59 resistant, 35 sensitive; median age 58 [range 27-75] years; 86 with performance status [PS] < or = 1). Forty-nine patients received a starting dose of 120 mg/m2, of which 15 escalated to 150 mg/m2, and 45 received a starting dose of 150 mg/m2. Overall, the median number of treatment cycles received was 3 (range 1-8). Grade 3/4 thrombocytopenia was the most common haematological adverse event occurring in 62% of patients overall. Grade 3/4 lethargy, vomiting and nausea were the most common non-haematological toxicities. No clinically significant oto-, nephro- or neurotoxicity was observed. Overall response rates for all platinum-resistant and -sensitive patients were 8.3% and 32.4%, respectively. Stable disease occurred in 17 resistant and 15 sensitive patients.

Adult↗
PubMed2002

Effects of a stay-green mutation on plant nitrogen relations in Lolium perenne during N starvation and after defoliation.

The stay-green mutation of the nuclear gene sid results in inhibition of chlorophyll degradation during leaf senescence in grasses, reducing N remobilization from senescing leaves. Effects on growth of Lolium perenne L. were investigated during N starvation (over 18 d) and after severe defoliation, when leaf growth depends on the remobilization of internal N. Rates of dry mater production, partitioning between shoots and roots, and re-partitioning of N from shoots to roots were very similar in stay-green and normal plants under N starvation. Km and Vmax for net uptake of NH4+ were also similar for both genotypes, and Vmax increased with the duration of N deprivation. The mutation had little effect on recovery of leaf growth following severe defoliation, but stay-green plants recommenced NO3- and K+ uptake 1 d later than normal plants. Import of remobilized N into new leaves was generally similar in both lines. However, stay-green plants remobilized less N from stubble compared with normal plants. It was concluded that the sid locus stay-green mutation has no significant adverse effect on the growth of L perenne during N starvation, or recovery from severe defoliation when plants are grown under an optimal regime of NO3- supply both before and after defoliation. The absence of any effect on leaf dry matter production implies that the difference in foliar N availability attributable to this mutation has little bearing on productivity, at least in the short to medium term.

Algorithms↗
PubMed2001

A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a monogenic, autosomal dominant subtype of early-onset diabetes mellitus due to defective insulin secretion by the pancreatic beta-cell in humans. Five different genes have been identified including those encoding the tissue-specific transcription factors expressed in pancreatic beta-cells, i.e. HNF-4alpha (MODY1), HNF-1alpha (MODY3), IPF-1 (also known as PDX-1, MODY4) and HNF-1beta (MODY5). Analyzing the transcription of the HNF-4alpha gene, we now identify an alternative promoter, P2, which is 46 kb 5' to the previously identified P1 promoter of the human gene. Based on RT-PCR this distant upstream P2 promoter represents the major transcription site in pancreatic beta-cells, but is also used in hepatic cells. Transfection assays with various deletions and mutants of the P2 promoter reveal functional binding sites for HNF-1alpha, HNF-1beta and IPF-1, the other transcription factors known to encode MODY genes. We demonstrate the significance of this alternative promoter in a large MODY family where a mutated IPF-1 binding site in the P2 promoter of the HNF-4alpha gene co-segregates with diabetes (LOD score 3.25). These data suggest a regulatory network of the four MODY transcription factors interconnected at the distant upstream P2 promoter of the HNF-4alpha gene.

Adult↗
PubMed2001

Serotonergic lesion of median raphe nucleus alters nerve growth factor content and vulnerability of cholinergic septohippocampal neurons in rat.

About 45% of the serotonergic raphe neurons are reported to express nerve growth factor (NGF) receptors. We therefore investigated whether selective serotonergic lesions of the median or dorsal raphe nuclei are associated with changes in NGF protein levels of the brain and whether the loss of serotonergic function alters the vulnerability of cholinergic septohippocampal neurons. In adult rats the hippocampal NGF content changed in a biphasic way after lesion of the median raphe nucleus by 5,7-dihydroxytryptamine (5,7-DHT), with a significant increase after 2-3 weeks of up to 35%, followed by a significant reduction of 22% below control levels after 7 weeks, and a return to control levels within the following 4 weeks. By contrast, the decrease in hippocampal serotonin and 5-hydroxyindoleacetic acid remained throughout the observation period of 11 weeks, being still reduced to 15 and 30% of the control levels, respectively. In the frontal cortex the partial loss of the serotonergic innervation projecting from the median raphe was associated 5 weeks after 5,7-DHT injection with an increase in NGF protein of 39.7+/-9.6% (P<0.05), which remained elevated up to 11 weeks. At 9 weeks after 5,7-DHT, the lesion of the septohippocampal cholinergic neurons induced by the cholinotoxin ethylcholine aziridinium (AF64A) was exaggerated (P<0.05) as compared to AF64A-treated rats with intact serotonergic innervation. The present data indicate that a serotonergic lesion of the median raphe nucleus results in biphasic changes of NGF protein content and in a delayed increase in the vulnerability of septohippocampal cholinergic neurons.

5,7-Dihydroxytryptamine↗
PubMed2001

Characterization of novel HLA-DR11-restricted HCV epitopes reveals both qualitative and quantitative differences in HCV-specific CD4+ T cell responses in chronically infected and non-viremic patients.

The CD4+ T cell response is of critical importance in determining the fate of many viral infections. Clearance of HCV has a strong association with the MHC class II antigen HLA-DR11 suggesting a key role for CD4+ T cells. We used an epitope-prediction program to identify multiple novel HLA-DR11-restricted epitopes derived from several HCV proteins. These epitopes then allowed us to explore the qualitative and quantitative aspects of specific CD4+ T cell responses in HLA-DR11+ patients. Irrespective of the time since viral clearance, all the non-viremic patients recognized four epitopes with a high frequency of IFN-gamma-producing memory CD4+ T cells. There appeared to be two subpopulations of memory cells, immediate "effector" memory cells (Th1 phenotype) and resting "central" memory cells (Th1/0). Chronically infected patients revealed an almost complete absence of HCV epitope-specific IFN-gamma-producing T cells. However, three of these epitopes induced IL-10 production (down-regulatory) raising the question as to whether these cells play a role in viral persistence. The frequency and phenotype of memory cells is likely to reflect the magnitude of the initial immune response, and suggests that a high frequency of IFN-gamma-secreting CD4+ T cells to multiple epitopes are important in clearance of HCV.

Antigens, Viral↗
PubMed2001

Internet-assisted exercises in structural analysis.

In this report we describe our experience in the analytical chemistry curriculum of teaching spectrometer principles and preparing spectroscopy laboratory exercises by means of virtual instruments. The benefits of the intensified preparation of laboratory exercises by virtual instruments will be evaluated with respect to the subsequent handling of real instruments. The utilization of in-house electronic media with Internet resources for elucidation and verification of a structural assignment will also be considered.

Journal Article↗
PubMed2001

Evidence from DNA that the mysterious 'linh duong' (Pseudonovibos spiralis) is not a new bovid.

In 1993, several horns of an unknown mammal were collected in the south of Vietnam. Due to the unusual characteristics of its horns, the 'linh duong', as named by Vietnamese hunters, was quickly described as belonging to a new monospecific genus of bovid, i.e. Pseudonovibos spiralis Peter & Feiler, 1994. The taxonomic status of Pseudonovibos was a highly controversial subject, and it has been suggested that this enigmatic species may be related to three different groups of Bovidae: Antilopini (gazelles), Bovini (cattle, bisons, buffaloes), and Caprini sensu lato (goats, sheep and allies). To assess the phylogenetic relationships of the linh duong within the family Bovidae, two different DNA markers, the nuclear lactoferrin and the mitochondrial cytochrome b genes, were sequenced from bone samples of four trophies collected during 1925 in Indochina. Results show that the mysterious horns of linh duong belong to domestic cattle (Bos taurus). Thus, the linh duong is not a new mammal and the scientific name Pseudonovibos spiralis should be abandoned.

Animals↗
PubMed2001

The enigmatic new Indochinese bovid, Pseudonovibos spiralis: an extraordinary forgery.

In 1993, the discovery of several pairs of lyre-shaped horns with corrugations was recorded in Vietnam and regarded as evidence for a new, large bovid, later referred to as Pseudonovibos spiralis Peter & Feiler, 1994. Despite numerous field investigations made since 1994 in Vietnam and Cambodia, no new anatomical evidence has ever been found, except for two frontlets with their horn cores and horn sheaths. A new investigation has been carried out on six frontlets and based on a histological analysis of the keratin. It shows that the horns of P. spiralis are merely a skillful forgery made by carving and distorting ordinary cow horns. The horns of Pseudonovibos spiralis were, in some cases, positioned back onto the corresponding horn cores of domestic cow frontlets. The name Pseudonovibos spiralis is thus a junior synonym of Bos taurus, yet it remains valid and available.

Animals↗
PubMed2001

Androgenesis from Festuca pratensis x Lolium multiflorum amphidiploid cultivars in order to select and stabilize rare gene combinations for grass breeding.

Androgenesis using amphidiploid cultivars of Festuca pratensis x Lolium multiflorum as parents, overcame earlier problems that gave rise to widespread plant sterility amongst androgenic Festulolium populations. Two Festuca pratensis x Lolium multiflorum (2n = 4x = 28) cultivars, Sulino and Felopa, were highly amenable to androgenesis and 10% of plants, including some novel androgenic genotypes, had sufficient fertility to produce progeny and further generations. The genomes of amphidiploid cultivars, which represent the F8 generation, were the result of considerable intergeneric chromosome recombination. Moreover, during cultivar development, natural and breeders' selection pressures had led to the assembly of gene combinations that conferred good growth characters and fertility with the removal of putative deleterious gene combinations. Over 80% of the androgenic plants derived from the amphidiploid F. pratensis x L. multiflorum (2n = 4x = 28) had 14 chromosomes and were likely to be dihaploids with a single genome of Lolium and of Festuca. In contrast, hybrids of F. pratensis x L. multiflorum (2n = 2x = 14) found naturally are invariably sterile. Structural reorganization within the genomes of the androgenic Festulolium plants had restored fertility in genotypes expected to contain the haploid genome of Lolium and Festuca. This provided opportunities for their future incorporation in breeding programmes and the development of fertile diploid Lolium-Festuca hybrids. Amongst the androgenic plants, Festulolium genotypes were recovered that conferred excellent drought resistance or freezing tolerance and were thought to be highly suitable for entry into plant breeding programmes.

Adaptation, Physiological↗
PubMed2001

Ovarian cancer chemotherapy.

The treatment of ovarian cancer has evolved over the past two decades from one of palliation to one where patients can achieve prolonged remission and cure. Although prognosis remains poor, it has improved with the intervention of a multidisciplinary team and greater site specialization in the organization of cancer services. The introduction of new chemotherapy agents both as first line treatment and on relapse has had a benefit in terms of overall survival and progression-free survival. In this review we describe first-line therapy, including the use of intraperitoneal chemotherapy, the importance of dose and dose intensity in platinum agents and the treatment of refractory and relapsed disease. Finally the review focuses on important prognostic factors and how these can be used to predict outcome.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Prospective validation of renal function-based carboplatin dosing in children with cancer: A United Kingdom Children's Cancer Study Group Trial.

PURPOSE: Carboplatin dosing in adults with cancer is based on renal function. The purpose of the current study was to validate a previously developed pediatric carboplatin-dosing formula. PATIENTS AND METHODS: Thirty-eight pediatric patients were randomized to receive a carboplatin dose calculated according to surface area or a renal function-based dosing formula. On the next course of therapy, the alternative dosing method was used for each patient. Carboplatin pharmacokinetics (based on free plasma platinum concentrations) were measured after both courses. RESULTS: The mean observed areas under the carboplatin concentration-versus-time curve (AUCs) after renal function- and surface area-based dosing were 98% and 95% of the target AUCs, respectively. The variation in the observed AUC was significantly less after renal function-based dosing (F test, P =.02), such that 74% of courses had an observed AUC within +/- 20% of the target value, versus 49% for courses after dosing according to surface area. Only one of 22 courses at the center with the most experience with renal function-based dosing was associated with an AUC outside +/- 20% of the target value, versus nine of 22 courses after surface area-based dosing in the same center. There was a relationship (r(2) =.71) between carboplatin AUC and thrombocytopenia in 10 neuroblastoma patients treated with a combination of carboplatin, vincristine, etoposide, and cyclophosphamide. CONCLUSION: Renal function-based carboplatin dosing in children results in more consistent drug exposure than surface area-based drug administration.

Adolescent↗
PubMed2000

A sensitivity analysis on the atmospheric transformation and deposition of mercury in north-eastern USA

This paper presents the results of a sensitivity analysis on the factors that affect dry and wet deposition of atmospheric mercury (Hg), using a regional scale air quality model. Simulations were conducted for the north-eastern USA during a summer week and a winter week in 1997. Simulation results for the summer week and the winter week in general showed similar responses to changes in emission, environmental conditions, and alternative chemical mechanisms. Reduction of the ambient concentrations of soot or ozone was shown to reduce the wet deposition of Hg. When averaged over the summer and the winter week, the total deposition to the simulation domain would be reduced by 26% by reducing Hg emission from anthropogenic sources within the domain by 50%. For individual grids, however, only locations near local sources obtained noticeable reductions in ambient concentration and wet deposition due to the influence of re-emission from the natural surfaces and regional/global scale transport. The reduction in deposition would reach 36% if all Hg(II) emitted from anthropogenic sources were attached to particles. The total deposition was predicted to decrease by 22% when the gas phase Hg(II)-Hg(p) partitioning was included in the model. Only small changes in total deposition were observed by including the gas-phase ozone-Hg(0), reaction and the aqueous phase chlorine-Hg(0), reaction, and by lowering ambient concentrations of Hg(II) and Hg(p) at the upper lateral boundaries. During the summer week, Hg(II) deposition contributed 40% or more to the total deposition. The contribution increased to 70% in the winter week.

Journal Article↗