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1.  A comparison of the efficacy of darifenacin alone vs. darifenacin plus a Behavioural Modification Programme upon the symptoms of overactive bladder 
Purpose
This study assessed the benefit of adding behavioural modification to darifenacin treatment for overactive bladder (OAB).
Materials and methods
The ABLE trial was a randomised, open-label, parallel-group, multicentre study of 12 weeks of darifenacin treatment [with voluntary up-titration from 7.5 mg once daily (qd) to 15 mg qd at week 2] alone or in combination with a Behavioural Modification Programme (BMP) for men and women with dry or wet OAB. Efficacy was assessed as the change in the number (per day) of micturitions (primary variable), urge urinary incontinence (UUI) episodes, urgency episodes, pads used and nocturnal voids. Health-related quality of life (HRQoL) was also evaluated. Tolerability and safety assessments included adverse events and the number of discontinuations.
Results
Of 592 patients screened, 395 were randomised, 190 to darifenacin alone and 205 to darifenacin + BMP. At baseline, the majority of subjects were dry (mean 2.8 and three UUI episodes per day in the darifenacin and darifenacin + BMP groups respectively). At study end, darifenacin alone and darifenacin + BMP both produced significant reductions from baseline in median numbers of micturitions, UUI episodes, urgency episodes and nocturnal voids (all p < 0.05), but not in the number of pads used. HRQoL also improved. There were no significant differences between treatment groups in efficacy or HRQoL variables.
Conclusions
Darifenacin treatment provides a degree of normalisation of micturition variables and improvement in HRQoL that cannot be further enhanced by behavioural therapy of the type used in this study. Whether behavioural modification would add benefit over darifenacin treatment in patients with more pronounced incontinence problems remains to be determined.
doi:10.1111/j.1742-1241.2008.01714.x
PMCID: PMC2325270  PMID: 18324952
3.  Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women 
Gut  2004;53(10):1452-1458.
Background and aims: Serotonin (5-hydroxtryptamine, 5-HT) is an important factor in gut function, playing key roles in intestinal peristalsis and secretion, and in sensory signalling in the brain-gut axis. Removal from its sites of action is mediated by a specific protein called the serotonin reuptake transporter (SERT or 5-HTT). Polymorphisms in the promoter region of the SERT gene have effects on transcriptional activity, resulting in altered 5-HT reuptake efficiency. It has been speculated that such functional polymorphisms may underlie disturbance in gut function in individuals suffering with disorders such as irritable bowel syndrome (IBS). The aim of this study was to assess the potential association between SERT polymorphisms and the diarrhoea predominant IBS (dIBS) phenotype.
Subjects: A total of 194 North American Caucasian female dIBS patients and 448 female Caucasian controls were subjected to genotyping.
Methods: Leucocyte DNA of all subjects was analysed by polymerase chain reaction based technologies for nine SERT polymorphisms, including the insertion/deletion polymorphism in the promoter (SERT-P) and the variable tandem repeat in intron 2. Statistical analysis was performed to assess association of any SERT polymorphism allele with the dIBS phenotype.
Results: A strong genotypic association was observed between the SERT-P deletion/deletion genotype and the dIBS phenotype (p = 3.07×10−5; n = 194). None of the other polymorphisms analysed was significantly associated with the presence of disease.
Conclusions: Significant association was observed between dIBS and the SERT-P deletion/deletion genotype, suggesting that the serotonin transporter is a potential candidate gene for dIBS in women.
doi:10.1136/gut.2003.035451
PMCID: PMC1774243  PMID: 15361494
irritable bowel syndrome; 5-HT; serotonin transporter; polymorphism
4.  Apoptosis in erythroid progenitors deprived of erythropoietin occurs during the G1 and S phases of the cell cycle without growth arrest or stabilization of wild-type p53. 
Molecular and Cellular Biology  1994;14(6):4183-4192.
Erythropoietin (Epo) inhibits apoptosis in murine proerythroblasts infected with the anemia-inducing strain of Friend virus (FVA cells). We have shown that the apoptotic process in FVA cell populations deprived of Epo is asynchronous as a result of a heterogeneity in Epo dependence among individual cells. Here we investigated whether apoptosis in FVA cells correlated with cell cycle phase or stabilization of p53 tumor suppressor protein. DNA analysis in nonapoptotic FVA cell subpopulations cultured without Epo demonstrated little change in the percentages of cells in G1,S, and G2/M phases over time. Analysis of the apoptotic subpopulation revealed high percentages of cells in G1 and S, with few cells in G2/M at any time. When cells were sorted from G1 and S phases prior to culture without Epo, apoptotic cells appeared at the same rate in both populations, indicating that no prior commitment step had occurred in either G1 or S phase. Steady-state wild-type p53 protein levels were very low in FVA cells compared with control cell lines and did not accumulate in Epo-deprived cultures; however, p53 protein did accumulate when FVA cells were treated with the DNA-damaging agent actinomycin D. These data indicate that erythroblast apoptosis caused by Epo deprivation (i) occurs throughout G1 and S phases and does not require cell cycle arrest, (ii) does not have a commitment event related to cell cycle phase, and (iii) is not associated with conformational changes or stabilization of wild-type p53 protein.
Images
PMCID: PMC358784  PMID: 8196656
5.  Mutant p53 tumor suppressor alleles release ras-induced cell cycle growth arrest. 
Molecular and Cellular Biology  1991;11(3):1344-1352.
Overexpression of an activated ras gene in the rat embryo fibroblast line REF52 results in growth arrest at either the G1/S or G2/M boundary of the cell cycle. Both the DNA tumor virus proteins simian virus 40 large T antigen and adenovirus 5 E1a are able to rescue ras induced lethality and cooperate with ras to fully transform REF52 cells. In this report, we present evidence that the wild-type activity of the tumor suppressor gene p53 is involved in the negative growth regulation of this model system. p53 genes encoding either a p53Val-135 or p53Pro-193 mutation express a highly stable p53 protein with a conformation-dependent loss of wild-type activity and the ability to eliminate any endogenous wild-type p53 activity in a dominant negative manner. In cotransfection assays, these mutant p53 genes are able to rescue REF52 cells from ras-induced growth arrest, resulting in established cell lines which express elevated levels of the ras oncoprotein and show morphological transformation. Full transformation, as assayed by tumor formation in nude mice, is found only in the p53Pro-193-plus-ras transfectants. These cells express higher levels of the ras protein than do the p53Val-135-plus-ras-transfected cells. Transfection of REF52 cells with ras alone or a full-length genomic wild-type p53 plus ras results in growth arrest and lethality. Therefore, the selective event for p53 inactivation or loss during tumor progression may be to overcome a cell cycle restriction induced by oncogene overexpression (ras). These results suggest that a normal function of p53 may be to mediate negative growth regulation in response to ras or other proliferative inducing signals.
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PMCID: PMC369405  PMID: 1996096
6.  Integration of Friend murine leukemia virus into both alleles of the p53 oncogene in an erythroleukemic cell line. 
Journal of Virology  1988;62(12):4752-4755.
The Friend virus-transformed erythroleukemic cell line DP16-9B4 has undergone a complex rearrangement of the p53 oncogene and lacks any detectable expression of the p53 protein. We report here characterization of both p53 alleles in this cell line and identify independent integrations of Friend murine leukemia virus sequences into the coding region of both alleles.
Images
PMCID: PMC253591  PMID: 2846884
7.  Distribution and effects of 2,4,5-trichlorophenoxyacetic acid in cells of Bacillus megaterium. 
Applied Microbiology  1975;30(6):959-963.
Cell death in a resting population of an asporogenous Bacillus megaterium was accelerated by ambient concentrations of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) equal to or greater than 10 mug/ml or 5 mug/mg of cells (dry weight), but only after prolonged exposure. Conversely, populations of growing cells were not markedly influenced even at 100 mug/ml. Effects on cell respiration were not manifest until the ambient concentration reached 1,000 mug of 2,4,5-T/ml, or 500 mug/mg. Cells of B. megaterium did, however, accumulate 2,4,5-T passively to a level approximately twofold above the ambient concentration. Most of the accumulated compound was easily washed from the cells, but, of the firmly bound herbicide, about 0.5 mug/mg of cells (dry weight), nearly 60% by weight, was localized in the protoplast membrane. The foregoing results, obtained with a purified preparation of 2,4,5-T were also elicited by 2,4,5-T analytical standards. The extracted contaminants did not produce the results alone nor did they influence the results when present in combination with 2,4,5-T.
PMCID: PMC376575  PMID: 813578
8.  Location and Consequences of 1,1,1-Trichloro-2,2-bis(p-Chlorophenyl) Ethane Uptake by Bacillus megaterium 
Applied Microbiology  1973;25(3):381-387.
No detrimental effects of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) were observed when cells of Bacillus megaterium were grown from small inocula in nutrient media containing up to 100 μg of DDT/ml. However, when the ratio of DDT to biomass of resting cells was held constant, levels of DDT as low as 1 μg/ml (0.5 μg/mg of cell dry weight) enhanced the rate of death in the population. The lethal action of DDT was both time- and dose-dependent so that higher doses required less time to effect the same killing than did lower doses. Intact cells bound a maximum of about 1.7 μg of DDT/mg of cell dry weight, of which about 75% was localized in the protoplast membrane. Much of the bound DDT was subsequently lost to the suspending medium and the aqueous stability of the returned DDT was enhanced, possibly by association with solubilized cell materials. A small quantity of bound DDT was converted to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane, which was released from cells somewhat faster than DDT. Apparently the lethal action of DDT was related to its binding in the membrane, but respiration was not inhibited. The atypical macroscopic appearance of membranes isolated from treated cells suggested that cell death may result from altered membrane chemistry.
PMCID: PMC380815  PMID: 4633425

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