J-2 Laboratories, located in Tucson, AZ, conducted saliva cotinin

J-2 Laboratories, located in Tucson, AZ, conducted saliva cotinine measurement by method of gas chromatographic thermionic specific detector. Intervention conditions selleck chemicals Ponatinib BP counseling. ��BP�� counseling is based on the Agency for Healthcare Research Quality practice guidelines for identifying patients who smoke and intervening for smoking cessation (Katz, Muehlenbruch, Brown, Fiore, & Baker, 2004; Windsor et al., 2000). Best practices is a five-step strategy, referred to as the ��5 A��s,�� which involves: (a) asking all patients about smoking status, (b) advising patients to quit, (c) assessing readiness to quit, (d) assisting through counseling or referral, and (e) arranging for follow-up. Participants were also given American Cancer Society literature on prenatal smoking cessation and the toll-free number for the quit smoking hotline.

Nurses at UCRC were trained by investigators in the use of this counseling strategy. All nurses attended two training sessions prior to study initiation and a refresher in-service midstudy. Nurses were instructed to keep counseling sessions to 10�C15 min whenever possible to mimic what would likely occur in usual practice. All BP counseling sessions were tape-recorded and monitored by investigators. Ultrasound feedback. In addition to providing routine ultrasound results, the ultrasound session was designed to provide information regarding cigarette smoke��s adverse effects on the fetus using a motivational style.

Four certified sonographers at the University of Texas Medical School Faculty Obstetrics and Gynecology clinic were trained to deliver risk messages related to smoking during the course of a comprehensive real-time fetal ultrasound with two initial 1-hr training sessions and a subsequent booster session. Sonographers were issued a laminated card containing major intervention messages to carry in their lab coat pockets for reference. They had the opportunity to practice and become comfortable with the delivery of the intervention messages via 30 pilot cases. Ultrasound sessions were tape-recorded for quality control, and sonographers were retrained as necessary. Ultrasound sessions lasted approximately 30 min.

Smoking risk messages were incorporated into discussion of anatomical features and included mention of the vasoconstricting effects of nicotine in the umbilical cord and placenta, reducing oxygen and nutrients to the fetus; accumulation of the poisonous gas CO in amniotic fluid and ingested by the fetus; possible premature Carfilzomib separation of the placenta from the uterus; and smoking effects that lead to premature delivery and/or low birth weight. For the majority of ultrasounds in which no complications were discovered, sonographers summarized by confirming that the baby was okay or unaffected at the time, noting, however, that the third trimester was the most likely time for problems to develop.

Because these bars are particularly popular with youth and may of

Because these bars are particularly popular with youth and may offer new tobacco marketing opportunities, scholars have called for waterpipes and other products to be included under tobacco control purview (Cobb, Ward, Maziak, Shihadeh, & Eissenberg, following 2010; Maziak, 2011). POS advertising is also an FCTC implementation challenge. Although some countries, such as Ukraine and the United Kingdom, have passed legislation to ban all POS activity (Bonner, 2012; ��Tobacco displays at the point of sale,�� 2012), this form of indirect marketing is still prevalent, even in countries with strict marketing restrictions. Researchers have called for POS advertising bans, p
Smokeless tobacco (SLT) use is growing in the United States and the last several years have seen a change in the SLT marketplace with the acquisition of two major SLT companies by cigarette companies and the introduction of new SLT product styles under cigarette brand names (e.

g., Camel Snus, Camel Dissolvables, Marlboro Snus) (Mejia & Ling, 2010). Research attention has focused on SLT use (e.g., Rodu & Cole, 2009; Timberlake & Huh, 2009), health risks (e.g., Boffetta, Hecht, Gray, Gupta, & Straif, 2008; Boffetta & Straif, 2009), harm-reduction potential (e.g., Foulds, Ramstrom, Burke, & Fagerstrom, 2003; Hatsukami, Lemmonds, & Tomar, 2004; Levy et al., 2004), and risk perceptions (e.g., O��Connor, Hyland, Giovino, Fong, & Cummings, 2005; O��Connor et al., 2007; Tomar & Hatsukami, 2007). However, few studies have examined mediated communications about SLT (Phillips, Wang, & Guenzel, 2005; Waterbor et al.

, 2004) and none have examined coverage of SLT in the news. Such research is significant given that the news media has played an important role in informing the public about tobacco��s dangers since the 1950s (Pierce & Gilpin, 2001). The news media also plays a broader role than transferring information to the public��by deeming certain topics newsworthy it defines which issues are ��important�� (McCombs & Shaw, 1972; Preiss, Gayle, Burrell, Allen, & Bryant, 2007). News coverage can also influence opinions and attitudes by shaping how we think about issues given their framing (National Cancer Institute [NCI], 2008). As such, analysis of tobacco news coverage is important for understanding which issues are perceived as important, how the problem of tobacco is being defined for the public and policy makers, and the types of solutions suggested (Lima & Siegel, 1999).

Analysis of tobacco news can also reflect and help us understand existing attitudes and public sentiment toward tobacco issues (Smith et al., 2008). Letters to the editor and op-ed articles provide a public forum where members of the public and tobacco control professionals can debate and express their views about timely tobacco issues (Clegg Smith, Wakefield, Batimastat & Edsall, 2006).

One possibility is that there were differences in nicotine concen

One possibility is that there were differences in nicotine concentrations by menstrual phase or depressive status that such were not able to be quantified and, therefore, the results underestimate the differences between groups. However, the frequency of undetectable levels did not appear to vary by menstrual phase (F: n = 13; L: n = 16) nor depressive symptoms status (NDS: n = 15; DS: n = 16) . In post-hoc analyses, excluding participants with any undetectable levels of serum nicotine, the overall results were largely unchanged (data not shown). Second, it is unknown how these observations may apply to smoking cessation efforts. It is well known that women receive less benefit from NRT (e.g., Bjornson et al., 1995; Perkins & Scott, 2008).

Our results suggest that women may receive less beneficial effects from nicotine replacement during the luteal phase because lower levels of nicotine are achieved, accounting for higher relapse in this phase in studies that have used the nicotine patch. Finally, our results are limited by our relatively small sample size, which limits our power to detect smaller differences in the physiological response to nicotine by menstrual phase and/or depressive symptoms status. Despite these limitations, this study has several strengths including its detailed measurement of menstrual phase, sex hormones, depressive symptoms status, and smoking status. Further, the randomized crossover study design is a strength of this study as this type of design limits the bias and confounding typically occurring in other study designs.

In conclusion, this study provides further evidence for the role of sex hormones and depressive symptoms on physiological response to nicotine in women. Although additional research is needed to further characterize the role of menstrual phase and depressive symptoms on risk for smoking relapse in women, these observations should be taken into consideration in the development of new smoking cessation interventions. FUNDING This project was funded by National Institute on Drug Abuse (NIDA) grant R01 DA08075. This publication was made possible by support from the National Center for Research Resources (NCRR) grant M01 RR00400, a component of the National Institutes of Health (NIH).

Additional support comes from the National Center for Research Resources (NCRR) grant 1UL1RR033183 and National Center for Advancing Translational Sciences (NCATS) grant 8UL1TR000114-02 of the NIH to the University of Minnesota Clinical and Translational Science Dacomitinib Institute (CTSI). The University of Minnesota CTSI is part of a national Clinical and Translational Science Award (CTSA) consortium created to accelerate laboratory discoveries into treatments for patients. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of CTSI, NIDA, NCRR, NCATS, or NIH.

Smoking cessation services Five minutes of brief smoking cessatio

Smoking cessation services Five minutes of brief smoking cessation advice by physicians could increase quit rates from about 5% at baseline to about 15% at follow-up (Folsom & Grimm, 1987; Janz et al., 1987; Russell, Wilson, Taylor, & Baker, 1979). The current U.S. policies promote the ��five A’s�� (ask, advise, assess, assist, and arrange) and encouraging physicians to ask and advise their patients figure 2 not to smoke. While more physicians are delivering brief advice, more research is needed to learn how to promote such advice from all health care providers. If all providers employed brief advice, the cumulative effects might be significant. The most affordable interventions are likely to be brief advice, but they tend to be the least powerful.

A subset of clinicians��for example, preventive medicine specialists��might offer more intensive interventions. This might include medications such as nicotine replacement therapy and Zyban for assisting with cessation. Some services are a good fit for this type of care. Families returning regularly for well-baby visits might be provided intensive clinical services by the pediatrician or assistants using tailored counseling, feedback, and incentives. Interventions could also provide financial and social contingencies to motivate cessation. Financial contingencies include vouchers��for example, $50/month to pregnant women for quitting smoking (Donatelle, Prows, Champeau, & Hudson, 2000), or $100 to employees for completing a smoking cessation program (Volpp et al., 2009).

Social contingencies include social support provided by a nonsmoker who has a close relationship with the smoker (Donatelle et al.). More research is needed in these promising areas. ��Minimal interventions�� for SHSe Minimal interventions for SHSe have not yet been tested. In a randomized trial with more than 2,000 families, Wall, Severson, Andrews, Lichtenstein, and Zoref (1995) provided minimal counseling and video materials for maternal smokers and explained that quitting would protect their child from SHSe and its health consequences. Parents were shown a video at the first well-baby visit and were provided written materials and brief advice from the pediatrician at well-baby visits at 2 weeks and 2, 4, and 6 months. This resulted in 7-day abstinence of 2.7% in control families and 5.9% in experimental families at 6 months.

However, the study focused on smoking cessation outcomes. No SHSe measures were obtained to determine whether changes in SHSe were obtained in homes, or whether parents smoked outside. Had this study included measures of SHSe, it might have demonstrated a direct effect on SHSe. Future studies should determine the likely effect of brief and low-intensity interventions for SHSe that could be distributed across many Carfilzomib clinical services.

81; BIS-Att 0 70; BIS-Mot 0 65; and BIS-NP 0 60: Stanford et al ,

81; BIS-Att 0.70; BIS-Mot 0.65; and BIS-NP 0.60: Stanford et al., 2009). Compared with normative values of the BIS-11 (Stanford et al., 2009), the population mean of BIS-11 scores was high��just less than 1 SD above normative scores. Table 1. Dependent Measures Obtained From Smokers, Assessing Age, Time Smoking, Impulsivity (BIS-11), Measures of Nicotine JQ1 msds Dependence (CDS-5 and DSM), Number of Cigarettes Smoked Per Day (Number), and Illicit Drug Use (ASMA) Association of BIS-11 With Measures of Dependence We observed modest correlations between BIS-11 total score and its subscales with the measures of tobacco use, dependence and craving, and illegal drug use (Table 2). Although these were generally positive, only a small number reached a Bonferroni-corrected significance level of 0.0025.

It was not the case that the relationship between smoking and impulsivity was determined by illegal drug use: A sub group of participants scoring 0 or 1 on the ASMA scale (n = 174) showed similar levels of associations between BIS-11 Total impulsivity score and measures of nicotine dependence. Table 2. Measures of Association (Spearman��s �� and accompanying p values) Between BIS-11 Impulsivity Scales and Measures of Nicotine Dependence (CDS-5 and DSM), Number of Cigarettes Smoked Per Day (Number), Days Smoking Per Week (Days), and Illicit … Association of BIS-11 With DSM Symptoms Consistent with our hypotheses, presence of both DSM5 and DSM7 symptoms was predicted by variation in total BIS-11 scores using logistic regression. Higher total BIS-11 scores led to an increased likelihood of endorsing the DSM5 (odds ratio [OR[ = 1.

030, 95% CI = 1.010�C1.051, df = 1, p = .0035) and DSM7 symptom (OR = 1.029, 95% CI = 1.005�C1.053, df = 1, p = .016). Of the three BIS-11 subscales, the DSM5 symptom was predicted by the motor subscale (OR = 1.098, 95% CI = 1.048�C1.15, df = 1, p < .001) but not the other two subscales. Similarly, the DSM7 symptom was predicted by motor (OR = 1.058, 95% CI = 1.003�C1.12, df = 1, p = .038) and non-planning impulsivity (OR = 1.050, 95% CI = 1.00�C1.10, df = 1, p = .047). None of the associations between total BIS-11 scores and other DSM symptoms reached significance at an alpha level of .05 (Figure 1). Figure 1. Odds ratios (ORs), which reflect the magnitude of the effect of BIS total score on likelihood of endorsement of a Diagnostic and Statistical Manual (DSM) symptom, are displayed.

ORs are ordered by their magnitude, and stars represent significant regression … Discussion In the present study, we sought more clearly to characterize the association between impulsivity and drug use in a large group of individuals with varying levels of tobacco usage recruited from a predominantly student population. First, the population showed a very high level Carfilzomib of impulsivity as measured by the Barratt Impulsiveness Scale (BIS-11: Patton et al., 1995; Stanford et al.

Because gender differences have been observed in adolescent smoki

Because gender differences have been observed in adolescent smoking patterns (Johnston et al., 2012) and in the association between sensation seeking and smoking (Doran et al., 2011), the effects of gender were examined in all the predictive models. In addition, because the prevalence of adolescent smoking varies selleck chemical Lenalidomide as a function of parental socioeconmic status (SES) (Soteriades & DiFranza, 2003), we included free or reduced lunch, an indicator of SES, as a covariate in all models. For those participants who had already completed the assessment at age 20/21, membership in the adolescent smoking classes was related to age 20/21 hookah use and cigarette use. METHOD Design and Sample The sample consisted of 963 children (487 girls and 476 boys) from the Oregon Youth Substance Use Project, 684 of whom had completed the age 20/21 assessment at the time of this report.

This is a longitudinal investigation of the etiology of substance use for which five grade cohorts (1st�C5th grades at the first assessment) of students from 15 elementary schools within one school district in Western Oregon were recruited and assessed annually or biennially. At age 20/21, participants were invited for an extensive in-person assessment at Oregon Research Institute. These assessments are ongoing. Using stratified random sampling (by school, grade, and gender), 2,127 students were invited to participate via invitations to their parents. Parents of 1,075 children gave consent for their child to participate (50.7%). At the first assessment (T1), an average of 215 students in each of the grade cohorts participated (N = 1,075; 50.

3% female) and the mean age at T1 was 9.0 years (SD = 1.45). Participants were representative of children in the school district in terms of race/ethnicity (i.e., primarily White) and participation in the free or reduced school lunch program (40%), but the 3rd and 5th grade cohorts had slightly higher achievement test scores on reading and math (for more details, see Andrews, Tildesley, Hops, Duncan, & Severson, 2003). To be included in the present study, participants had to have participated in at least one assessment when they were in 9th�C12th grades. The comparison of these 963 children with the 112 not included in this study (10% attrition) showed no differences on gender, free or reduced lunch, ethnicity, or sensation seeking.

Cohort differences examined at each grade identified only a few nonsystematic differences in sensation seeking, and no differences for smoking, so annual assessments were collapsed across cohorts to model the growth of sensation seeking from 4th AV-951 to 8th grade and the growth of smoking across 9th�C12th grade. Measures and Procedures Sensation Seeking This trait was measured by self-report questionnaire using three high-loading items from the Thrill and Adventure seeking subscale of the Sensation Seeking scale for elementary and middle school children developed by Russo et al.

For this reason observational

For this reason observational selleckbio studies were undertaken and these indirect data were used to support efficacy. For instance, the NIH registry [9] suggested that individuals who received therapy for at least 6 months had not just a reduction in mortality but also a modulation of the FEV1 decline for those with baseline values in the range 35-60% predicted. However, these data were likely influenced, at least in part, by availability of healthcare provision and social aspects of healthcare delivery in the USA. Nevertheless, other studies provided similar results by observing a greater decline in FEV1 in countries where augmentation was not available [10] and a reduction in decline after therapy was instigated [11].

Furthermore the former observation was also supported by a recent meta-analysis providing indirect evidence that spirometric decline is less where augmentation is available [12]. Nevertheless it is recognised that these observations, though supportive, cannot replace formal clinical trials. Importantly the NIH study, where used to support augmentation, has been interpreted as suggesting no benefit outside the FEV1 limits of 35-60% predicted and in some countries augmentation is stopped below this lower limit and not usually started above these limits. However recent data has indicated that using other more specific and sensitive measures of emphysema, such as the alveolar gas transfer and/or the decrease in lung density, indicate that progression of lung disease occurs both above and below these FEV1 limits [13,14], even when FEV1 remains stable as indicated in data summarised in Figure 1 for an individual patient from the UK National Registry.

Figure 1 The decline in FEV1 and Kco expressed as a % predicted is shown over time for a 43 year old female from the UK registry who stopped smoking after diagnosis in 2005. A recent Cochrane review took the pragmatic approach of analysing the efficacy of augmentation therapy based on the results of decline in FEV1 of the Drug_discovery only 2 small placebo controlled trials available [15,16] and concluded that there was no convincing data to support the efficacy of augmentation therapy [17]. However, both studies were just short of conventional statistical significance in favour of the efficacy of augmentation therapy using lung densitometry as the outcome. Combining the 2 studies and excluding all individuals who participated in the first (less robust study) from the second (more robust study) was however highly suggestive of efficacy in reducing the rate of decline in lung density [18], which is validated and has become accepted as the most specific and sensitive measurement of the progression of emphysema [13,19,20].

Loci were excluded if they

Loci were excluded if they Ceritinib LDK378 were monoallelic (n=5), had less than 95% genotyping success (n=22), or had Hardy�CWeinberg p values of less than .01 (��2, n=5). In total, only 22 of the 33 SNPs (67%) from the NICSNP high-density association study and 115 of the 137 SNPs (84%) from the candidate gene study provided usable genotyping information. The surviving 137 SNPs were then analyzed using an ordinal regression analysis and an additive genetic model to identify SNPs significantly associated with nicotine dependence. To maintain internal consistency with our previous publications, our primary data analyses were conducted using DSM-IV nicotine dependence counts. However, to make these results more consistent with those conducted by the NICSNP Consortium and more useful to all investigators, where appropriate, we have provided parallel regression analyses using the FTND data.

Both these symptom counts were treated as ordinal variables. Where appropriate, intermarker disequilibrium between SNPs at each candidate gene locus was calculated using Haploview (Stephens, Smith, & Donnelly, 2001). Haplotypes for genes with at least one significantly associated SNP were inferred using PHASE (Stephens et al., 2001), as described previously (Bradley, Dodelzon, Sandhu, & Philibert, 2005). Haplotypes with frequencies greater than 0.10 were then incorporated as additive factors in ordinal regression analyses that sometimes included sex and nicotine exposure data, as described in the text, using JMP Genomics, SAS version 9.1, and the chi-square test. All test results reported are two-tailed.

Results The demographic and clinical characteristics of the sample population are described in Tables 1 and and2.2. The sample is largely White and predominantly female. Consistent with intentional loading of the sample cohorts for the genetic diatheses for substance use, there are high levels of nicotine use. Some 90% of subjects reported smoking at least once in their lifetime and 51% reported smoking at least 100 cigarettes in their lifetime. Table 1. Subject demographics and characteristics Table 2. DSM-IV nicotine dependence symptom counts and Fagerstr?m Test for Nicotine Dependence (FTND) scores As a first step in our analyses, we conducted ordinal regression analyses of nicotine dependence symptom counts with respect to genotype at each of the 137 SNPs that survived quality assurance assessment using DSM-IV nicotine dependence symptom counts and an additive model (Philibert, Ryu, et al.

, 2007; Philibert, Sandhu, et al., 2007). In total, 12 SNPs were nominally associated with nicotine dependence (p < .05 before correction for multiple comparisons); all these were from the candidate gene analysis (Table 3). Six of these SNPs were from CHRNA2, three were from CHRNA7, three were from CHRNB1, and one was from CHRNA1. In general, the correlation between results obtained using DSM-IV symptom counts and our secondary analyses AV-951 of FTND scores was quite good.

After a further wash, cells were suspended in PBS containing 2% F

After a further wash, cells were suspended in PBS containing 2% FCS and analysed on a FACScan flow cytometer (Becton-Dickinson and Co., San Jose, CA, USA). To label dead cells, 0.5��gml?1 propidium iodide was added to the cells before analysis. Irrelevant monoclonal IgG antibodies (at equivalent concentrations) were used as isotype http://www.selleckchem.com/products/Roscovitine.html controls. Determination of p42/p44 MAP kinase/extracellular signal regulated kinase (ERK), FLIP and caspase-8 by Western blotting Cells were grown in the presence of FCS, deprived of serum for 24h and exposed or not to ET-1 for 10min. Cell cultures were extracted using 0.1% Triton X-100 in the presence of a cocktail of protease inhibitors (Roche, Rotfzreuz, Switzerland) and submitted to SDS electrophoresis.

Following transfer, the membrane was probed using monoclonal antiphosphorylated p42/p44 antibody (clone E10) (New England Biolabs, Bioconcepts, Alschwill, Switzerland) as previously described (Egidy et al, 2000c). Alternatively, cell extracts were exposed following blotting to anti-caspase-8 (New England Biolabs), anti-FLIP (a kind gift of J Tschopp, Lausanne, Switzerland) or anti ��-SMA (Sigma, Buchs, Switzerland) monoclonal antibodies. Calculations of results Each experiment was repeated at least three times unless otherwise stated. Means and s.d. were calculated. Statistical significance was assessed using an unpaired two-tailed Student’s t-test. RESULTS Expression of the ET-1 system in human colon and colon carcinoma cells The presence of immunoreactive ET-1 was assessed in human normal colon (Figure 1A, upper panel) and colon carcinoma (Figure 1A, lower panel).

Cancer cells, but not normal epithelial cells, ubiquitously expressed ET-1. The expression of the mRNAs of the components of the ET system in HT-29 and SW480 human colon carcinoma Batimastat cells was evaluated using RT�CPCR. ETA and ETB receptors, ECE-1 and PPET-1 mRNAs confirmed the presence of all the transcripts of the ET system in these cells (Figure 1B). Figure 1 Imunnohistochemical localisation of ET-1 and expression of the mRNAs of the ET-1 pathway in human colon carcinoma cells. (A) ET-1 immunoreactivity is ubiquitously localised in tumour cells of colon carcinoma (lower panel), but not in nontumoral epithelial … Confluent cultures of SW480 (4��104cellscm?2) and HT-29 (5��104cellscm?2) cells secreted ET-1, either in the absence or presence of FCS (Figure 1C). The presence of cell membrane and functional ET-1 receptors in SW480 and HT-29 cells was evaluated using 125I-ET-1 binding (Figure 1D) and the phosphorylation of ERK, a known intracellular mediator of ET-1 (Figure 1E).

Patients were treated for colorectal cancer and received chemothe

Patients were treated for colorectal cancer and received chemotherapy consisting of leucovorin 20mgm?2 plus 5-fluorouracil kinase inhibitor Sunitinib 425mgm?2. Blood sampling was carried out on day 1 of the first cycle. The 5-fluorouracil area under the curve0��3h in the index patient was 24.1mghl?1 compared to 9.8��3.6 (range 5.4�C15.3) mghl?1 in control patients. The 5-fluorouracil clearance was 520mlmin?1 vs 1293��302 (range 980�C1780) mlmin?1 in controls. The activity of dihydropyrimidine dehydrogenase in mononuclear cells was lower in the index patient (5.5nmolmgh?1) compared to the six controls (10.3��1.6, range 8.0�C11.7nmolmgh?1). Sequence analysis of the dihydropyrimidine dehydrogenase gene revealed that the index patient was heterozygous for a IVS14+1G>A point mutation.

Our results indicate that the inactivation of one dihydropyrimidine dehydrogenase allele can result in a strong reduction in 5-fluorouracil clearance, causing severe 5-fluorouracil induced toxicity. British Journal of Cancer (2002) 86, 1028�C1033. DOI: 10.1038/sj/bjc/6600199 www.bjcancer.com ? 2002 Cancer Research UK Keywords: DPD, 5-fluorouracil, pharmacokinetics, DPYD gene, mutation, pharmacogenetics Fluorouracil (5-FU) is widely used in chemotherapeutic regimens for the treatment of breast-, colorectal- and head- and neck cancer. The cytotoxic mechanism of 5-FU is complex, requiring intracellular bioconversion of 5-FU into cytotoxic nucleotides (see Figure 1). Inhibition of thymidylate synthase by the metabolite 5-fluoro-2��-deoxyuridine-5��-monophosphate is thought to be the main mechanism of cytotoxicity (Pinedo and Peters, 1988) .

The cytotoxicity is caused by only a small part of the administered 5-FU dose, as the majority of 5-FU is rapidly metabolised into inactive metabolites. The initial and rate-limiting enzyme in the catabolism of 5-FU is dihydropyrimidine dehydrogenase (DPD), catalysing the reduction of 5-FU into 5,6-dihydrofluorouracil (DHFU). Several groups have suggested a major role of DPD in the regulation of 5-FU metabolism and thus in the amount of 5-FU available for cytotoxicity (Harris et al, 1990; Fleming et al, 1992a; Lu et al, 1993; Etienne et al, 1994). Indeed, in patients with DPD enzyme deficiency, 5-FU chemotherapy is associated with severe, life-threatening toxicity (Van Kuilenburg et al, 2000a). Moreover, a markedly prolonged elimination half-life of 5-FU has been observed in a patient with complete deficiency of DPD enzyme activity (Diasio et al, 1988). Several mutations in the dihydropyrimidine dehydrogenase gene (DPYD), which encodes Brefeldin_A for the DPD enzyme have recently been identified (Van Kuilenburg et al, 2000a; Collie-Duguid et al, 2000).