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Biomedical subjects

G A Thomas

Publications and source records attributed to G A Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2001

Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy.

The clinical syndrome of encephalopathy is most often encountered in the context of decompensated liver disease and the diagnosis is usually clear cut. Non-hepatic causes of encephalopathy are rarer and tend to present to a wide range of medical specialties with variable and episodic symptoms. Delay can result in the development of potentially life threatening complications, such as seizures and coma. Early recognition is vital. A history of similar episodes or clinical risk factors and early assessment of blood ammonia levels help establish the diagnosis. In addition to adequate supportive care, investigation of the underlying cause of the hyperammonaemia is essential and its reversal, where possible, will often result in complete recovery. Detection of an unborn error of metabolism should lead to the initiation of appropriate maintenance therapy and genetic counselling.

Adult↗
PubMed2001

DNA replication licensing and human cell proliferation.

The convergence point of growth regulatory pathways that control cell proliferation is the initiation of genome replication, the core of which is the assembly of pre-replicative complexes resulting in chromatin being "licensed" for DNA replication in the subsequent S phase. We have analysed regulation of the pre-replicative complex proteins ORC, Cdc6, and MCM in cycling and non-proliferating quiescent, differentiated and replicative senescent human cells. Moreover, a human cell-free DNA replication system has been exploited to study the replicative capacity of nuclei and cytosolic extracts prepared from these cells. These studies demonstrate that downregulation of the Cdc6 and MCM constituents of the replication initiation pathway is a common downstream mechanism for loss of proliferative capacity in human cells. Furthermore, analysis of MCM protein expression in self-renewing, stable and permanent human tissues shows that the three classes of tissue have developed very different growth control strategies with respect to replication licensing. Notably, in breast tissue we found striking differences between the proportion of mammary acinar cells that express MCM proteins and those labelled with conventional proliferation markers, raising the intriguing possibility that progenitor cells of some tissues are held in a prolonged G1 phase or "in-cycle arrest". We conclude that biomarkers for replication-licensed cells detect, in addition to actively proliferating cells, cells with growth potential, a concept that has major implications for developmental and cancer biology.

Animals↗
PubMed2001

Capillary electrophoresis-based heteroduplex analysis with a universal heteroduplex generator for detection of point mutations associated with rifampin resistance in tuberculosis.

BACKGROUND: Slab gel heteroduplex analysis (HDA), a popular scanning method for genetic mutations, uses DNA fragments typically generated by PCR to create homo- and heteroduplex molecules with conformational differences and sequence-dependent electrophoretic profiles. Use of a universal heteroduplex generator (UHG) enhances the subtle variations caused by single-base substitutions. METHODS: The HDA-UHG slab gel format was modified for an efficient capillary-based method. The effect of staining dyes TOPRO5 and YOPRO1 on the analysis of heteroduplexes was studied, as well as ultraviolet absorbance and laser-induced fluorescence (LIF) detection methods. In addition, the entangled polymers hydroxyethyl cellulose, methyl cellulose, and linear polyacrylamide were evaluated as separation matrices. RESULTS: This assay was able to detect the presence of Mycobacterium tuberculosis and its rifampin susceptibility directly from clinical specimens in dramatically reduced analysis time (30 min vs 2.5 h). Optimized conditions included 0.3% methyl cellulose as the separation matrix, on-line staining using 1 micromol/L YOPRO1, and LIF detection for quantitative and reproducible analysis of single-base substitutions in the rifampin resistance-determining region of rpoB that give rise to the rifampin-resistant phenotype of M. tuberculosis. We generated 95% confidence limits using the wild-type sequence and used these limits to determine rifampin susceptibility in samples. CONCLUSIONS: Capillary electrophoresis, combined with the HDA-UHG technique, may be of value for rapid and efficient clinical diagnosis of rifampin-resistant tuberculosis strains.

Amino Acid Sequence↗
PubMed2000

Functional assessment of skeletal muscle ventricles after pumping for up to four years in circulation.

BACKGROUND: The successful treatment of cardiac failure by heart transplantation is severely limited by the shortage of donor organs, and alternative surgical approaches are needed. An experimental approach that holds considerable promise is the skeletal muscle ventricle (SMV), an auxiliary blood pump formed from a pedicled graft of latissimus dorsi muscle and connected to the circulation in a cardiac assist configuration. Adaptive transformation, or conditioning, by electrical stimulation enables the skeletal muscle to perform a significant proportion of cardiac work indefinitely without fatigue. METHODS: In 10 dogs, SMVs were constructed from the latissimus dorsi muscle, lined internally with pericardium, and conditioned by electrical stimulation to induce fatigue resistant properties. The SMVs were connected to the descending thoracic aorta via two 12-mm Gore-Tex conduits and the aorta was ligated between the two grafts. The SMV was stimulated to contract during the diastolic phase of alternate cardiac cycles. The animals were monitored at regular intervals. RESULTS: At initial hemodynamic assessment, SMV contraction augmented mean diastolic blood pressure by 24.6% (from 61 +/- 7 to 76 +/- 9 mm Hg). Presystolic pressure was reduced by 15% (from 60 +/- 8 to 51 +/- 7 mm Hg) after an assisted beat. Four animals died early, 1 from a presumed arrhythmia, and 3 during propranolol-induced hypotension. The other 6 animals survived for 273, 596, 672, 779, 969, 1,081, and 1,510 days. Diastolic augmentation was 27.4% at 1 year (93 +/- 9 vs 73 +/- 6 mm Hg; n = 5), 34.7% at 2 years (85 +/- 6 vs 63 +/- 7 mm Hg; n = 3), 21.2% (89 +/- 10 vs 73 +/- 8 mm Hg; n = 2) at 3 years, and 34.5% (78 vs 58 mm Hg; n = 1) after 4 years in circulation. After 4 years, the isolated SMV was able to maintain a pressure of over 80 mm Hg while ejecting fluid at 20 mL/s. No animal showed evidence of SMV rupture or thromboembolism. CONCLUSIONS: The SMVs in this study provided effective and stable hemodynamic assistance over an extended period of time. There was no evidence that the working pattern imposed on the muscular wall of the SMV compromised its viability. Areas of fibrofatty degeneration were suggestive of early damage that future protocols should seek to minimize.

Animals↗
PubMed2000

Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis.

BACKGROUND: Ulcerative colitis is a condition of nonsmokers in which nicotine is of therapeutic benefit. AIMS: To examine the in vitro effect of nicotine on colonic smooth muscle activity and the role of nitric oxide (NO) as a mediator. METHODS: Nicotine, 1-10 microM, was administered to strips of circular muscle from the distal sigmoid colon of 9 patients with active ulcerative colitis and 18 with colorectal cancer. The effect of electrical field stimulation (EFS) was examined before nicotine was added. Finally L-NAME, a NO synthetase inhibitor, was added before nicotine was administered again. RESULTS: Muscle strips developed similar spontaneous resting tone. In response to EFS, ulcerative colitis tissue developed lower tensions than the controls. Nicotine significantly reduced the resting tone and peak tension after EFS, with a greater effect in controls. With L-NAME, peak tensions were increased more in ulcerative colitis than controls, and nicotine produced a much smaller reduction. CONCLUSIONS: Nicotine reduces circular muscle activity, predominantly through the release of nitric oxide-this appears to be 'up-regulated' in active ulcerative colitis. These findings may explain some of the therapeutic benefit from nicotine (and smoking) in ulcerative colitis and may account for the colonic motor dysfunction in active disease.

Adult↗
PubMed2000

Gene rearrangement and Chernobyl related thyroid cancers.

The increase in thyroid carcinoma post-Chernobyl has been largely confined to a specific subtype of papillary carcinoma (solid/follicular). This subtype is observed predominantly in children under 10 in unirradiated populations, but maintains a high frequency in those aged 10-15 from those areas exposed to fallout from the Chernobyl accident. The aim of this study was to link morphology with molecular biology. We examined 106 papillary carcinomas from children under the age of 15 at operation. All were examined for rearrangements of the RET oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of these cases were also examined for mutations of the three ras oncogenes, exon 10 of the thyroid stimulating hormone receptor, associated more usually with a follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53 gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of the REToncogene were found in 44% of papillary carcinomas in which we studied fresh material; none of the tumours examined showed mutation in any of the other genes. The two rearrangements resulting from inversion of part of chromosome 10 (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with PTC1 being associated with papillary carcinomas of the classic and diffuse sclerosing variants and PTC3 with the solid/follicular variant.

Adolescent↗
PubMed2000

Crohn's disease incidence in Cardiff from 1930: an update for 1991-1995.

OBJECTIVE: To report the incidence of Crohn's disease in the city of Cardiff between 1991 and 1995, in relation to the data of the preceding 65 years. METHODS: The incidence of Crohn's disease was studied by collecting information from clinical records, the department of pathology database and a questionnaire sent to local family practitioners. RESULTS: Eighty-four new patients with Crohn's disease, and resident in Cardiff, were diagnosed between 1991 and 1995. The mean incidence for this quinquennium was 56 cases per 10(6) population per year (95% confidence interval, 44-68). There was a female predominance, particularly in young adults, with an overall male to female ratio of 0.47. Colorectal disease was the most common site of disease at the time of diagnosis. CONCLUSIONS: In relation to the findings of our previous studies, the data suggest that the overall incidence of Crohn's disease is now stable, but that the proportion with colorectal disease continues to increase and there is a marked female preponderance in Crohn's disease presenting in young people.

Adolescent↗
PubMed2000

Role of smoking in inflammatory bowel disease: implications for therapy.

The relationship between smoking and inflammatory bowel disease is now firmly established but remains a source of confusion among both patients and doctors. It is negatively associated with ulcerative colitis but positively associated with Crohn's disease. In addition, it has opposite influences on the clinical course of the two conditions with benefit in ulcerative colitis but a detrimental effect in Crohn's disease. These differences have been the subject of much interest and scrutiny with the hope that they may offer some insight into the pathogenesis of the two conditions and possibly lead to alternative therapeutic options. Nicotine is probably the principal active ingredient in smoking responsible for the association; trials have shown it to be of some benefit in ulcerative colitis, but further research is required to establish its therapeutic role, and the relevant mechanisms responsible for its action. In this article, we review the role of smoking in inflammatory bowel disease and its implication for therapy.

Colitis, Ulcerative↗
PubMed1999

Acute lymphoblastic leukemia with the (8;14)(q24;q32) translocation and FAB L3 morphology associated with a B-precursor immunophenotype: the Pediatric Oncology Group experience.

Five pediatric patients are described with acute lymphoblastic leukemia (ALL) who at presentation had clinical findings suggestive of B cell ALL and lymphoblasts with FAB L3 morphology and the characteristic t(8;14)(q24;q32). However, the leukemia cells of all five patients failed to express surface immunoglobulin (sIg) and kappa or lambda light chains. Based on initial immunophenotyping results consistent with B-precursor ALL, four of these cases were initially treated with conventional ALL chemotherapy. These four patients were switched to B cell ALL treatment protocols once cytogenetic results became available revealing the 8;14 translocation. The fifth case was treated with B cell ALL therapy from the outset. Four of the five patients are in complete remission at 64, 36, 29 and 13 months from diagnosis. One patient relapsed and died 6 months after initial presentation. These five unusual cases with clinical B cell ALL, the t(8;14), and FAB L3 morphology, but negative sIg, demonstrate the importance of careful and multidisciplinary evaluation of leukemic cells with morphology, cytochemistry, immunophenotyping and cytogenetic analysis. Future identification of patients with this profile will allow us to expand our knowledge regarding prognostic significance and optimal treatment for this rare subgroup of patients.

Adolescent↗
PubMed1999

An oral formulation of nicotine for release and absorption in the colon: its development and pharmacokinetics.

AIMS: Ulcerative colitis is predominantly a disease of nonsmokers and transdermal nicotine has therapeutic value in active disease; however side-effects are troublesome. The aim of this study was to develop an oral formulation of nicotine which would be slowly released in the colon over 6 h, and to examine its pharmacokinetic profile in 12 healthy volunteers, with measurements of serum nicotine and cotinine, its principal metabolite. METHODS: Nicotine was combined with a polyacrylic carbomer, Carbopol 974P which was incorporated into 13 different vehicles and their release profiles examined in vitro. The polyglycolized glyceride, Gelucire 50/13, was chosen for subsequent kinetic studies because it consistently produced a suitable release pattern which was linear. Capsules containing 3 mg nicotine, combined with carbomer in Gelucire 50/13, were coated with an acrylic resin Eudragit L; this ensured the capsule would remain intact until the ileum. On 2 separate days, 6 and 15 mg nicotine, contained in 2 and 5 capsules, respectively, were administered to 12 subjects, all nonsmokers, mean age 28 years. Serial blood measurements were taken for 36 h, serum nicotine and cotinine concentrations were measured by gas liquid chromatography. RESULTS: There was considerable intersubject variability in the nicotine and cotinine values. Plasma nicotine levels began to rise about 4 h after ingestion of the capsules, corresponding with the oro-caecal transit time. Cmax nicotine values were 2.2 and 5 ng ml-1, obtained 7 h after the ingestion of 6 and 15 mg, respectively, of the formulation. The corresponding Cmax values for cotinine were 37 and 94.4 ng ml-1, occurring after 9-10 h. The mean for elimination half-lives in the 24 studies, including the 6 and 15 mg doses, for nicotine were 4.3+/-2.7 h and for cotinine 16.8+/-7.5 h. With 6 mg nicotine-carbomer, only 1 of 12 volunteers had possible side-effects, but with the 15 mg dose 11 out of the 12 reported adverse effects which were systemic or gastrointestinal in nature-their timing corresponded with peak serum concentrations of nicotine. CONCLUSIONS: An oral formulation of nicotine has been developed; in the ileum and colon, this becomes available for slow linear release over 6 h and delivers high concentrations of nicotine for topical effect on the colon. 6 mg Nicotine was well tolerated, whilst 15 mg gave both systemic and gastrointestinal side-effects. High concentrations of topical nicotine in the colon are achieved with relatively low systemic bioavailablity-reflected by the Cmax and AUC values for nicotine. This, or comparable formulations, may be of therapeutic value in ulcerative colitis.

Absorption↗