Biomedical subjects
Publications and source records attributed to T Cook.
The use of Chinese herbal remedies is increasing in the UK. We report the presence of a nephrotoxic compound in herb samples, which led to end-stage renal failure in two patients. We suggest that use of these products is regulated more tightly.
The discovery and functional characterization of Sp1 as a GC-rich binding zinc finger protein provided a useful paradigm for understanding mechanisms mediating transcriptional activation in eukaryotic cells. This early paradigm suggested that promoters carrying GC-rich sequences are activated by Sp1 through its interaction with proteins from the basal transcriptional machinery to upregulate gene expression. Since the time of this seminal work, studies from several laboratories have led to the discovery of many Sp1-like transcription factors containing highly homologous DNA binding motifs that bind to similar sequences. Consequently, this knowledge poses many important questions regarding whether these related proteins have similar or antagonistic biochemical and functional properties to Sp1. The goal of this article is to use available database information and recent experimental evidence to describe the current repertoire of Sp1-like zinc finger transcription factors in mammalian cells. Furthermore, we discuss structural and functional studies that reveal that these proteins may share a role in morphogenetic pathways. Altogether, this information is aimed at better understanding how this growing family of transcription factors work to regulate gene expression and morphogenesis.
BACKGROUND: Both gemcitabine and docetaxel have been associated with pulmonary toxicity when used as single agents. We report a study in which three of five cases developed pulmonary toxicity (which proved fatal in one case) when these drugs were used in combination to treat metastatic transitional cell cancer. PATIENTS AND METHODS: Three patients developed dyspnoea, in two cases associated with pulmonary infiltrates, whilst receiving the combination of gemcitabine and docetaxel in a phase I trial. The case notes of all five patients entered into this trial were studied. A literature review was undertaken to gain information on reported pulmonary toxicity with the deoxy-cytidine analogues and taxanes given alone or in combination with or without radiotherapy. RESULTS: Three patients developed delayed dyspnoea whilst receiving gemcitabine/docetaxel in combination. This settled with cessation of treatment in one patient, however in the remaining two cases significant hypoxia developed, associated radiologically with evidence of progressive pulmonary infiltrates. One of these patients developed respiratory failure after bronchoscopy and biopsy and died. His chest X-ray changes were consistent with adult respiratory distress syndrome. The transbronchial biopsy and post mortem lung histology in this patient showed diffuse alveolar damage. The remaining patient settled with high dose prednisolone but died subsequently of progressive metastatic disease. CONCLUSION: The combination of gemcitabine and docetaxel showed promising activity in this small study. The development of pulmonary symptoms in three cases with radiological lung infiltrates in two other cases was cause for concern. Patients receiving this drug combination should be closely monitored for similar problems.
In utero somatic gene therapy in the later stages of pregnancy may allow targeting of organ systems which are difficult to reach later in life and to prevent the development of tissue damage otherwise caused by the early onset of inherited diseases. We report here on the percutaneous delivery of two adenoviral vectors, containing the beta-galactosidase reporter gene and the human Factor IX gene respectively, to the fetal liver and circulation by ultrasound-guided umbilical vein puncture similar to procedures used in human pregnancy. Vector spread, as detected by PCR analysis for the beta-galactosidase encoding vector, was found in almost all fetal and neonatal organs and in the maternal liver. Expression of the beta-galactosidase transgene was detected in many fetal tissues by RT-PCR. High beta-galactosidase production was shown by immuno-histochemistry predominantly in the liver, where about 30percent of the hepatocytes stained positive, and in the adrenal cortex. Production of factor IX was determined by ELISA in the plasma of treated fetuses and newborn lambs and reached at birth up to 80percent of the normal human plasma concentration. This demonstrates a very hopeful proof of principle for the development of prenatal treatment of many genetic diseases but also requires more detailed investigations with respect to the observed systemic spread of the vector.
Explore the source record for details and available documents.
Sedentary behavior is a major public health problem for African American women. A qualitative study used focus groups to explore African American women's experiences with physical activity in their daily lives. Women aged 35-50 were recruited to participate in the focus groups. Transcripts from the focus groups were coded and analyzed. African American women's facilitators of physical activity were daily routine, practical and convenient activities, personal safety, child care, weight loss, stress reduction, knowledge and commitment, enjoyment, pets, family and peer support, home and work facilities, and daylight and climate conditions. Barriers to physical activity were lack of child care, no person to exercise with, competing responsibilities, lack of space in the home, inability to use exercise facilities at work, lack of motivation, fatigue, and unsafe neighborhood. This information will provide the basis for generating new strategies to increase physical activity for African American women in the community.
Sp1-like zinc finger transcription factors are involved in the regulation of cell growth and differentiation. Recent evidence demonstrating that mammalian cells express novel, yet uncharacterized, Sp1-like proteins has stimulated a search for new members of this family. We and others have recently reported that the transforming growth factor (TGF)-beta-regulated gene TIEG encodes a new Sp1-like protein that inhibits cell growth in cultured cells. Here we report the identification, nuclear localization, DNA binding activity, transcriptional repression activity, and growth inhibitory effects of TIEG2, a novel TGF-beta-inducible gene related to TIEG. TIEG2 is ubiquitously expressed in human tissues, with an enrichment in pancreas and muscle. TIEG2 shares 91% homology with TIEG1 within the zinc finger region and 44% homology within the N terminus. Biochemical characterization reveals that TIEG2 is a nuclear protein, which, as predicted from the primary structure, specifically binds to an Sp1-like DNA sequence in vitro and can repress a promoter containing Sp1-like binding sites in transfected Chinese hamster ovary epithelial cells. Furthermore, functional studies using [3H]thymidine uptake and MTS (3-(4, 3-dimethyltiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-su lfophenyl)-2 H-tetrazolium) assays demonstrate that the overexpression of TIEG2 in Chinese hamster ovary cells inhibits cell proliferation. Thus, TIEG2, together with TIEG1, defines a new subfamily of TGF-beta-inducible Sp1-like proteins involved in the regulation of cell growth.
Renal function was assessed by measuring serum creatinine and glomerular filtration rate (GFR) in two groups of patients with chronic plaque psoriasis who had been treated with cyclosporin A (CyA), average dose 2.8 mg/kg per day (range 1-5 mg/kg per day). Group I was our original cohort of nine patients, seven of whom had received CyA for an average period of 10 years (range 9.5-11 years). These seven patients showed a persistent increase in serum creatinine > 30% from baseline measurement and four of the seven had persistent increases > 50%. The GFR, which was first measured after 2.5 years of treatment, showed at 10 years a decrease of > 30% in two patients and of > 50% in one patient. Three of the seven showed stable renal function while two had repeat renal biopsy because of deteriorating renal function and histology showed further evidence of CyA nephrotoxicity compared with that after 5 years' treatment. Two of the nine patients in group I had discontinued CyA 5 years previously after 5 years of treatment because of CyA nephrotoxicity on renal biopsy and impaired renal function. This impairment of renal function showed improvement during the 5 years of follow-up, implying reversibility of CyA nephrotoxicity. The second group of 20 patients had received CyA for an average duration of 6 years (range 5-8 years). Nine of the 20 patients showed persistent increases in serum creatinine of > 30% from baseline and five showed persistent increases of > 50%. The GFR showed a persistent decrease of > 30% in seven patients and of > 50% in two patients. This study has shown that nephrotoxicity is associated with long-term treatment with CyA. However, there is patient variation as to when nephrotoxicity commences and its speed of progression. On discontinuing CyA the impairment of renal function improves with time. Providing renal function is monitored with GFR and renal biopsy in addition to serum creatinine then long-term (5-10 years) CyA treatment can be justified in severe psoriasis not responsive to other treatments.
AIM: To assess differences in treatment of ischaemic heart disease in the Scandinavian countries. METHODS AND RESULTS: The Scandinavian Simvastatin Survival Study (4S) lasted 5.4 years and showed that death rates in 4444 patients with coronary heart disease were 30% lower in those treated with simvastatin to lower serum cholesterol than in those given placebo. Apart from this main result, the 4S provided detailed information on rates of death and other manifestations of coronary heart disease, as well as on use of non-lipid forms of therapy. There were substantial differences in 4S placebo group rates of mortality, coronary deaths and major coronary events between countries. Surgical and medical therapy varied importantly between countries. CONCLUSIONS: Major inter-country differences in rates of death and myocardial infarction in patients with coronary heart disease were likely to be due to a composite of differences in baseline characteristics including smoking. They occurred in a setting of very uneven exploitation of the potential for improving survival of patients with ischaemic heart disease.
A qualitative study was undertaken to explore the facilitators, barriers, and strategies that contribute to exercise performance in European American (EA) women. Focus groups were used to obtain information about the experiences of EA women concerning physical activity in their daily lives. Sixteen women aged 35-50 were recruited to participate in one of two focus groups. Focus group transcripts were coded and content analyzed. Major facilitators identified were social support, accommodating schedule, self improvement, supportive environment, and individual factors. Major barriers were lack of family support, unaccommodating schedule, consequences of exercise, environmental barriers, and individual barriers. The findings of this study can be used to develop nursing interventions designed to decrease sedentary behavior in EA women.
Explore the source record for details and available documents.
"On the night of the 1996 Census, 5.4 per cent of the people counted in Australia were staying away from home (visitors), compared to 4.6 per cent in 1986. Queensland's share of the nation's visitors has risen since 1986, largely at the expense of Western Australia's. Queensland is now the most popular destination for interstate and overseas visitors, while New South Wales hosts a large proportion of intrastate visitors. But the overall picture is partly obscured because the Census missed around 100,000 overseas visitors."
In the 7 years since dynamin was first isolated from bovine brain in search of novel microtubule-based motors, our understanding of this enzyme has expanded significantly. We now know that brain dynamin belongs to a family of large GTPases, which mediate vesicle trafficking. Furthermore, this enzymatic activity is markedly increased through association with microtubules, acidic phospholipids, and certain regulatory proteins that contain Src homology 3 (SH3) domains. From functional, genetic, and cellular manipulations, it is now generally accepted that dynamin participates in the endocytic uptake of receptors, associated ligands, and plasma membrane following an exocytic event. These observations have confirmed at least one function of dynamin that was predicted from seminal studies on a pleiotropic mutant, shibire(ts) (shi(ts)) in Drosophila melanogaster. Of equal interest is the finding that there are multiple dynamin gene products, including two that are expressed in a tissue-specific manner, and they share marked homology with a larger family of distinct but related proteins. Therefore, it is attractive to speculate that the different dynamins may participate in related cellular functions, such as distinct endocytic processes and even secretion. In turn, dynamin could play an important role in cell growth, cell spreading, and neurite outgrowth. The purpose of this review is to enumerate on the expansive dynamin literature and to discuss the nomenclature, expression, and putative functions of this growing and interesting family of proteins.
With the aim of developing foetal gene therapy for cystic fibrosis, we have investigated the possibility of gene targeting to the mouse foetus with two different viral vector systems and at different times of gestation. We report here that recombinant retrovirus producing cells administered into the intra-amniotic cavity of mid- to late-gestation mouse MF1 foetuses survive in the amniotic fluid and are able to engraft to a certain extent in foetal tissues. By production of infectious virus they mediate transduction and beta-galactosidase transgene expression in neighbouring foetal tissues 24 to 72 h following injection. Retrovirus producer cells could, therefore, become a means to overcome the limitations of low retroviral titre, for in vivo foetal gene transfer. To investigate the developmental stage at which transduction of the airways and enteral systems can be obtained we also administered a highly infective first generation adenoviral vector (AdRSV beta gal) into the amniotic cavity of foetal mice between 13 to 16 days post coitus, beta-galactosidase activity was detected between 24 to 120 h after injection. The highest levels of transgene expression were generally observed between 48 to 72 h following injection of the adenoviral vector. We demonstrate that infection of the pulmonary airways is dependent on the developmental stage of the foetus and can be achieved on the 15th day of gestation.
BACKGROUND: There is a high incidence of renal disease in the ethnically Indian population in the United Kingdom, the pathological basis for which is only partly understood. This study attempted to define associations between renal biopsy diagnosis and race. The aim was thereby to identify types of renal disease which may contribute to the observed predisposition to renal failure in the Indian population served by our centre. METHOD: A single-centre-based retrospective analysis of the final diagnosis and corresponding ethnicity in 394 consecutive patients undergoing native renal biopsy for the investigation of abnormal renal function or urinary sediment. RESULTS: A highly significant association between a diagnosis of interstitial nephritis and Indian race was observed. There were 30 cases of interstitial nephritis, of whom 17 were Indian. In 15 of the Indian patients no aetiology could be established. The clinical features, outcomes, and the effect of steroid therapy in the Indian patients with idiopathic interstitial nephritis are described. CONCLUSION: Idiopathic interstitial nephritis is associated with Indian racial origin. This pathology may significantly contribute to the high incidence of end-stage renal failure in Indian patients resident in the United Kingdom.
The Scandinavian Simvastatin Survival Study (4S) was a double-blind, randomized placebo-controlled multi-centre clinical trial of long-term Simvastatin therapy in patients with coronary heart disease who had total cholesterol levels between 5.5 and 8.0 mmol/l, comprising 4444 patients, equally distributed to a Simvastatin and a placebo group. Patients achieved a significant 30% relative reduction in overall mortality with Simvastatin therapy through a 42% relative reduction in coronary heart disease mortality. Lp(a) lipoprotein levels in Scandinavian coronary heart disease patients were strikingly higher than in healthy controls. Numbers of deaths in the Simvastatin group differed significantly between quartiles of Lp(a) lipoprotein levels, the reduction in deaths being most pronounced in the second (next to lowest) quartile. Subjects with major coronary events had significantly higher Lp(a) lipoprotein levels than subjects without such events, in all groups. The relationship between Lp(a) lipoprotein level and total mortality as well as between Lp(a) lipoprotein level and major coronary events was significantly different from zero, in logistic regression analyses. The findings show that Lp(a) lipoprotein predicts major coronary events as well as death in secondary prevention with Simvastatin. This prospective study provides independent confirmation that a high Lp(a) lipoprotein level is a significant coronary heart disease risk factor.
Explore the source record for details and available documents.
BACKGROUND: Although smoking increases both the risk of developing coronary disease and the risk of coronary events in patients with known coronary atherosclerosis, the effect of smoking on the evolution of coronary atherosclerosis as assessed by serial angiography is poorly defined. METHODS AND RESULTS: Ninety smokers with coronary atherosclerosis shown on a recent angiogram and with fasting cholesterol levels between 220 and 300 mg/dL were enrolled in a randomized, double-blind, placebo-controlled trial of cholesterol-lowering therapy, along with 241 nonsmokers and exsmokers. Lovastatin at a mean dose of 36 mg/d lowered total and LDL cholesterol by 21 +/- 11% and 29 +/- 11%, respectively, but these levels changed by < 2% in placebo-treated patients. Coronary arteriography was repeated after 2 years in 72 smokers and their 557 lesions were measured blindly with an automated quantitative system, along with 1752 lesions in 227 nonsmokers. Coronary change score, the per-patient mean of the minimal lumen diameter changes for all qualifying lesions, worsened by 0.16 +/- 0.16 mm in smokers and by 0.07 +/- 0.15 mm in nonsmokers in the placebo group (P < .001). Lovastatin-treated smokers had less worsening (0.07 +/- 0.15 mm) than placebo-treated smokers (P = .024). One or more coronary lesions progressed in 16 of 34 lovastatin-treated smokers and in 28 of 38 placebo-treated smokers (47% versus 74%, P < .001). In the placebo group, new coronary lesions developed in 21 of 38 smokers and in 28 of 115 nonsmokers (55% versus 24%, P < .001); fewer lovastatin-treated smokers developed new lesions (15% versus 55%, P < .001). CONCLUSIONS: Smoking accelerates coronary progression and new lesion formation as assessed by serial quantitative coronary arteriography. Lovastatin slows the progression of coronary atherosclerosis and prevents the development of new coronary lesions in smokers.