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Significant Dose (significant + dose)
Selected AbstractsInduction of V(D)J-mediated recombination of an extrachromosomal substrate following exposure to DNA-damaging agentsENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 6 2007Robert L. Pinsonneault Abstract V(D)J recombinase normally mediates recombination signal sequence (RSS) directed rearrangements of variable (V), diversity (D), and joining (J) germline gene segments that lead to the generation of diversified T cell receptor or immunoglobulin proteins in lymphoid cells. Of significant clinical importance is that V(D)J-recombinase-mediated rearrangements at immune RSS and nonimmune cryptic RSS (cRSS) have been implicated in the genomic alterations observed in lymphoid malignancies. There is growing evidence that exposure to DNA-damaging agents can increase the frequency of V(D)J-recombinase-mediated rearrangements in vivo in humans. In this study, we investigated the frequency of V(D)J-recombinase-mediated rearrangements of an extrachromosomal V(D)J plasmid substrate following exposure to alkylating agents and ionizing radiation. We observed significant dose- and time-dependent increases in V(D)J recombination frequency (V(D)J RF) following exposure to ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS) but not a nonreactive analogue, methylsulfone (MeSulf). We also observed a dose-dependent increase in V(D)J RF when cells were exposed to gamma radiation. The induction of V(D)J rearrangements following exposure to DNA-damaging agents was not associated with an increase in the expression of RAG 1/2 mRNA compared to unexposed controls or an increase in expression of the DNA repair Ku70, Ku80 or Artemis proteins of the nonhomologous end joining pathway. These studies demonstrate that genotoxic alkylating agents and ionizing radiation can induce V(D)J rearrangements through a cellular response that appears to be independent of differential expression of proteins involved with V(D)J recombination. Environ. Mol. Mutagen., 2007. © 2007 Wiley-Liss, Inc. [source] Defining success in clinical trials , profiling pregabalin, the newest AEDEUROPEAN JOURNAL OF NEUROLOGY, Issue 2005P. Ryvlin The efficacy and safety of pregabalin as adjunctive therapy for patients with partial epilepsy with or without secondary generalization has been established by four randomized, 12-week, double-blind, placebo-controlled trials (n = 1396) and four long-term open-label studies (n = 1480). Patients in the three fixed-dose trials were ,12 years of age, had ,6 partial seizures and no 4-week seizure-free period during the 8-week baseline period. Seventy-three per cent of patients were taking ,2 concomitant antiepileptic drugs. Responder rates across the effective doses (150,600 mg/day) ranged from 14% to 51% and demonstrated a significant dose,response relationship. The most common adverse events were central nervous system related, generally mild or moderate, transient, and tended to be dose related. The fourth placebo-controlled trial compared a fixed dose of pregabalin 600 mg/day with a flexible-dose regimen (150,600 mg/day). Responder rates were greater for both the fixed dose (45.3%, P < 0.001) and flexible dose (31.3%, P < 0.001) when compared with placebo (11.0%). Compared with the fixed-dose group, the flexible-dose patients had a lower incidence of adverse events and study discontinuations. In long-term open-label trials, the efficacy of pregabalin was maintained with respect to 50% responder rates suggesting no obvious tolerance developing over 2 years. Seizure-free rates were 8.9% and 5.8% for the last 6 months and 1 year of pregabalin treatment, respectively. Long-term open-label pregabalin treatment was well tolerated. [source] Neuromotor effects of short-term and long-term exposures to trichloroethylene in workers,AMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 9 2010Katsuyuki Murata MD Abstract Background Health effects of long-term exposure to organic solvents at low levels are a major concern in industrialized countries. To assess the neuromotor impact of trichloroethylene objectively, static postural sway and hand tremor parameters, along with urinary trichloroethanol (TCOH) and trichloroacetic acid (TCAA) levels, were investigated in 57 workers without obvious neurological disorders and 60 control subjects. Methods The workers had been occupationally exposed to trichloroethylene for 0.1,37 years. The cumulative exposure index (CEI) was calculated from their occupational history and total trichloro-compounds (TCOH,+,TCAA). Results Median levels in the workers were 1.7,mg/L for TCOH and 2.5,mg/L for TCAA, and the maximum ambient trichloroethylene concentration was estimated to be <22,ppm from the previously reported equation using TCOH,+,TCAA. Sway parameters with eyes open and tremor intensity in dominant hand were significantly larger in the exposed workers than in the control subjects when adjusting for possible confounders. A significant dose,effect association was seen between two sway parameters and urinary TCOH level in the workers. Tremor intensities in non-dominant hand differed significantly among three groups of the workers divided according to the CEI. Conclusions These findings suggest that trichloroethylene exposure, even at low levels of less than the short-term exposure limit by the ACGIH, can affect the neuromotor function of workers. The postural instability appears to result from recent exposure, and the increased tremor may occur due to short-term and long-term exposures. Hereafter, such objective measures, along with subjective symptoms, should be carefully used for the occupational exposure limit setting. Am. J. Ind. Med. 53:915,921, 2010. © 2010 Wiley-Liss, Inc. [source] Marked Variation of the Association of ESRD Duration Before and After Wait Listing on Kidney Transplant OutcomesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010J. D. Schold Numerous studies report a strong association between pretransplant end-stage renal disease (ESRD) duration and diminished transplant outcomes. However, cumulative waiting time may reflect distinct phases and processes related to patients' physiological condition as well as pre-existing morbidity and access to care. The relative impact of pre- and postlisting ESRD durations on transplant outcomes is unknown. We examined the impact of these intervals from a national cohort of kidney transplant recipients from 1999 to 2008 (n = 112 249). Primary factors explaining prelisting ESRD duration were insurance and race, while primary factors explaining postlisting ESRD duration were blood type, PRA% and variation between centers. Extended time from ESRD to waitlisting had significant dose,response association with overall graft loss (AHR = 1.26 for deceased donors [DD], AHR = 1.32 for living donors [LD], p values < 0.001). Contrarily, time from waitlisting (after ESRD) to transplantation had negligible effects (p = 0.10[DD], p = 0.57[LD]). There were significant associations between pre- and postlisting ESRD time with posttransplant patient survival, however prelisting time had over sixfold greater effect. Prelisting ESRD time predominately explains the association of waiting time with transplant outcomes suggesting that factors associated with this interval should be prioritized for interventions and allocation policy. The degree to which the effect of prelisting ESRD time is a proxy for comorbid conditions, socioeconomic status or access to care requires further study. [source] A multiparameter flow cytometric analysis of the effect of bexarotene on the epidermis of the psoriatic lesionBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2003M.E.J. Franssen Summary Background A new retinoid, bexarotene (Targretin®), was recently investigated in a large multicentre trial for its efficacy and safety in psoriasis. Bexarotene is a novel retinoid X receptor (RXR)-selective ligand. Objectives The aim was to study the effect of bexarotene in psoriasis by analysing markers for epidermal differentiation, proliferation and inflammation in epidermal single cell suspensions from lesions of patients with psoriasis treated with various doses of bexarotene. Methods Thirty-four patients with moderate to severe plaque psoriasis participated in this study and were assigned in sequence to four different dose regimens: 0·5, 1, 2 and 3 mg kg,1 once daily. Before and after 12 weeks of bexarotene treatment, punch biopsies were taken from lesional skin from which epidermal single cell suspensions were prepared using an optimized thermolysin protocol. A sum of scores was determined for each biopsy site, based on a four-point scale for erythema, induration and desquamation. An improved multiparameter flow cytometric assay was used that enabled simultaneous assessment of epidermal proliferation, various aspects of differentiation and epidermal inflammation. The following variables were measured simultaneously: relative DNA content, relative cell size, keratin (K) 10, K6 and vimentin expression. Results The psoriasis area and severity index (PASI) and sum of scores for the individual psoriatic lesion each showed a statistically significant decrease of 28% after 12 weeks of bexarotene treatment (P < 0·001). However, no significant dose,response effect was found. The total percentage of K10+ cells showed a significant increase of 43% (P < 0·01). The total population of K6 expressing cells did not show significant changes. Regarding the subpopulations of K6 single, K10 single and K6 and 10 co-expressing cells, a significant increase of 77% was seen in the K10+ K6, cells (P < 0·05), a significant decrease of 33% in K10, K6+ cells (P < 0·01), and no significant changes in the remaining population of K10+ K6+ cells. After 12 weeks of treatment with bexarotene no significant changes in epidermal proliferation and inflammation were shown. Conclusions The present study indicates a direct effect of RXR activation by bexarotene on the transition of proliferation-associated keratinization into normal keratinization. Although no direct effect of bexarotene on DNA content in the total K10, cells was shown, further studies on subpopulations within the germinative layer such as stem cells and transit amplifying cells might be worthwhile. [source] Indications of infection with Chlamydia pneumoniae are associated with expansion of abdominal aortic aneurysmBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 4 2000R. A. P. Scott Background: This was a study of the possible association between the progression of abdominal aortic aneurysm (AAA) and indicators of infection with Chlamydia pneumoniae. Methods: Blood samples were taken from patients with AAA (3 cm diameter or greater detected by an aneurysm screening programme) who had been followed prospectively for up to 11·5 (mean 4·1) years. A sex- and age-matched control group was also recruited. Immunoglobulin (Ig) G and IgA antibodies against C. pneumoniae were measured by a microimmunofixation test. Analysis of variance, multiple linear regression and logistic regression were used for statistical analysis. Ninety men and ten women with a small AAA and 20 age-matched male controls were investigated. Outcome measures studied were AAA expansion, and IgA and IgG titres of antibodies against C. pneumoniae. Results: Forty-four (95 per cent confidence interval (c.i.) 31,55) per cent of the men with an AAA had IgA greater than 64 or IgA above 28 compared with 10 per cent of the women with an AAA (odds ratio (OR) 7·2 (95 per cent c.i. 1·0,160·8)) and 25 per cent of the controls (OR 2·24 (95 per cent c.i. 0·67,7·93)). IgA greater than 128 was significantly associated with greater expansion (5·3 versus 2·6 mm per year), even after adjustment for initial AAA size and age. A significant dose,response reaction was found between IgA titre and mean annual expansion (R = 0·45 (95 per cent c.i. 0·24,0·62)). The significant positive correlation remained after adjusting for initial AAA size and age. Finally, IgG greater than 128 was present significantly more often in patients with expansion above 1 cm annually (OR 12·6 (95 per cent c.i. 1·4,293)). Conclusion: A high proportion of men with AAA have signs of infection by C. pneumoniae. The progression of AAAs correlated with the presence of indicators of C. pneumonia infection, and a dose,response reaction between IgA titre and expansion was observed. © 2000 British Journal of Surgery Society Ltd [source] How many cisplatin administration protocols does your department use?EUROPEAN JOURNAL OF CANCER CARE, Issue 1 2010A.P. GREYSTOKE bsc, mbchb, registrar medical oncology GREYSTOKE A.P., JODRELL D.I., CHEUNG M., RIVANS I. & MACKEAN M.J. (2009) European Journal of Cancer Care19, 80,90 How many cisplatin administration protocols does your department use? The introduction, 30 years ago, of the co-administration of appropriate hydration and ensuring a diuresis occurs during the administration of cisplatin was important in its development, allowing clinically significant doses to be given with acceptable rates of toxicity. The clinical usage of cisplatin has increased and hydration protocols have been amended to increase patient comfort and reduce resource utilization. We suspected that this had led to unnecessary variations in practice both in clinical trials and subsequently in the clinic. Therefore, we reviewed practice in the Edinburgh Cancer Centre and discovered that 25 different hydration protocols were in use, with wide variation in dilution of cisplatin, total fluid administered, use of electrolyte (potassium and magnesium) supplementation and diuretics. These differences are a reflection of adoption of variations in hydration regimes published in pivotal clinical trials. A review of the available evidence relating to cisplatin associated hydration regimens was performed and recommendations will be made for the future design of evidence-based protocols. [source] | ||||||||||