Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. We report lymphocytic DPD data concerning a group of 53 patients (23 men, 30 women, mean age 58, range 36–73), treated by 5-FU-based chemotherapy in different French institutions and who developed unanticipated 5-FU-related toxicity. Lymphocyte samples (standard collection procedure) were sent to us for DPD determination (biochemical method). Among the whole group of 53 patients, 19 had a significant DPD deficiency (DD; below 150 fmol min−1 mg−1 protein, i.e. less than 70% of the mean value observed from previous population study). There was a greater majority of women in the DD group (15 out of 19, 79%) compared with the remaining 34 patients (15 out of 34, 44%, P<0.014). Toxicity was often severe, leading to patient death in two cases (both women). The toxicity score (sum of WHO grading, theoritical range 0–20) was twice as high in patients with marked DD (below 100 pmol min−1 mg−1 protein, n = 11, mean score = 13.2) compared with patients with moderate DD (between 150 and 100 pmol min−1 mg−1 protein, n = 8, mean score = 6.8), P = 0.008. In the DD group, there was a high frequency of neurotoxic syndromes (7 out of 19, 37%). The two deceased patients both had severe neurotoxicity. The occurrence of cardiac toxicity was relatively rare (1 out of 19, 5%). These data suggest that women are particularly prone to DPD deficiency and allow a more precise definition of the DD toxicity profile. © 1999 Cancer Research Campaig

Targeted prevention of common mental health disorders in university students: randomised controlled trial of a transdiagnostic trait-focused web-based intervention

Background: A large proportion of university students show symptoms of common mental disorders, such as depression, anxiety, substance use disorders and eating disorders. Novel interventions are required that target underlying factors of multiple disorders.&lt;p&gt;&lt;/p&gt; Aims: To evaluate the efficacy of a transdiagnostic trait-focused web-based intervention aimed at reducing symptoms of common mental disorders in university students.&lt;p&gt;&lt;/p&gt; Method: Students were recruited online (n = 1047, age: M = 21.8, SD = 4.2) and categorised into being at high or low risk for mental disorders based on their personality traits. Participants were allocated to a cognitive-behavioural trait-focused (n = 519) or a control intervention (n = 528) using computerised simple randomisation. Both interventions were fully automated and delivered online (trial registration: ISRCTN14342225). Participants were blinded and outcomes were self-assessed at baseline, at 6 weeks and at 12 weeks after registration. Primary outcomes were current depression and anxiety, assessed on the Patient Health Questionnaire (PHQ9) and Generalised Anxiety Disorder Scale (GAD7). Secondary outcome measures focused on alcohol use, disordered eating, and other outcomes.&lt;p&gt;&lt;/p&gt; Results: Students at high risk were successfully identified using personality indicators and reported poorer mental health. A total of 520 students completed the 6-week follow-up and 401 students completed the 12-week follow-up. Attrition was high across intervention groups, but comparable to other web-based interventions. Mixed effects analyses revealed that at 12-week follow up the trait-focused intervention reduced depression scores by 3.58 (p&#60;.001, 95%CI [5.19, 1.98]) and anxiety scores by 2.87 (p = .018, 95%CI [1.31, 4.43]) in students at high risk. In high-risk students, between group effect sizes were 0.58 (depression) and 0.42 (anxiety). In addition, self-esteem was improved. No changes were observed regarding the use of alcohol or disordered eating.&lt;p&gt;&lt;/p&gt; Conclusions This study suggests that a transdiagnostic web-based intervention for university students targeting underlying personality risk factors may be a promising way of preventing common mental disorders with a low-intensity intervention

Quality of Care for HIV Infection Provided by Ryan White Program-Supported versus Non-Ryan White Program-Supported Facilities

BACKGROUND: The Ryan White HIV/AIDS Care Act (now the Treatment Modernization Act; Ryan White Program, or RWP) is a source of federal public funding for HIV care in the United States. The Health Services and Resources Administration requires that facilities or providers who receive RWP funds ensure that HIV health services are accessible and delivered according to established HIV-related treatment guidelines. We used data from population-based samples of persons in care for HIV infection in three states to compare the quality of HIV care in facilities supported by the RWP, with facilities not supported by the RWP. METHODOLOGY/PRINCIPAL FINDINGS: Within each area (King County in Washington State; southern Louisiana; and Michigan), a probability sample of patients receiving care for HIV infection in 1998 was drawn. Based on medical records abstraction, information was collected on prescription of antiretroviral therapy according to treatment recommendations, prescription of prophylactic therapy, and provision of recommended vaccinations and screening tests. We calculated population-level estimates of the extent to which HIV care was provided according to then-current treatment guidelines in RWP-supported and non-RWP-supported facilities. For all treatment outcomes analyzed, the compliance with care guidelines was at least as good for patients who received care at RWP-supported (vs non-RWP supported) facilities. For some outcomes in some states, delivery of recommended care was significantly more common for patients receiving care in RWP-supported facilities: for example, in Louisiana, patients receiving care in RWP-supported facilities were more likely to receive indicated prophylaxis for Pneumocystis jirovecii pneumonia and Mycobacterium avium complex, and in all three states, women receiving care in RWP-supported facilities were more likely to have received an annual Pap smear. CONCLUSIONS/SIGNIFICANCE: The quality of HIV care provided in 1998 to patients in RWP-supported facilities was of equivalent or better quality than in non-RWP supported facilities; however, there were significant opportunities for improvement in all facility types. Data from population-based clinical outcomes surveillance data can be used as part of a broader strategy to evaluate the quality of publicly-supported HIV care

Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene

5-fluorouracil pharmacokinetics, dihydropyrimidine dehydrogenase-activity and DNA sequence analysis were compared between a patient with extreme 5-fluorouracil induced toxicity and six control patients with normal 5-fluorouracil related symptoms. Patients were treated for colorectal cancer and received chemotherapy consisting of leucovorin 20 mg m−2 plus 5-fluorouracil 425 mg m−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 24.1 mg h l−1 compared to 9.8±3.6 (range 5.4–15.3) mg h l−1 in control patients. The 5-fluorouracil clearance was 520 ml min−1 vs 1293±302 (range 980–1780) ml min−1 in controls. The activity of dihydropyrimidine dehydrogenase in mononuclear cells was lower in the index patient (5.5 nmol mg h−1) compared to the six controls (10.3±1.6, range 8.0–11.7 nmol mg h−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

Discovery of Radio Emission from the Brown Dwarf LP944-20

Brown dwarfs are classified as objects which are not massive enough to sustain nuclear fusion of hydrogen, and are distinguished from planets by their ability to burn deuterium. Old (>10 Myr) brown dwarfs are expected to possess short-lived magnetic fields and, since they no longer generate energy from collapse and accretion, weak radio and X-ray emitting coronae. Several efforts have been undertaken in the past to detect chromospheric activity from the brown dwarf LP944-20 at X-ray and optical wavelengths, but only recently an X-ray flare from this object was detected. Here we report on the discovery of quiescent and flaring radio emission from this source, which represents the first detection of persistent radio emission from a brown dwarf, with luminosities that are several orders of magnitude larger than predicted from an empirical relation between the X-ray and radio luminosities of many stellar types. We show in the context of synchrotron emission, that LP944-20 possesses an unusually weak magnetic field in comparison to active dwarf M stars, which might explain the null results from previous optical and X-ray observations of this source, and the deviation from the empirical relations.Comment: Accepted to Natur

‘1L=10L for Africa’: Corporate social responsibility and the transformation of bottled water into a ‘consumer activist’ commodity

In recent years, it has become an increasingly common marketing practice to connect the sale of consumer products to corporate social responsibility (CSR) initiatives, such as aid and development projects in so-called ‘developing’ countries. One example is Volvic’s pioneering ‘1L=10L for Africa’ campaign (2005–2010), which linked the sale of each liter of bottled water in ‘developed’ countries with the promise by Danone, Volvic’s owner, to provide 10 liters of drinking water in Africa. In this article, we engage with this ‘cause-related marketing’ campaign, using critical discourse analysis (CDA) to uncover its mechanisms and ideological functioning. We show how Volvic was able to transform an ordinary commodity, bottled water, into a consumer activist brand through which consumers could take part in solving global social problems, such as the access to safe drinking water in ‘developing’ countries. Our analysis of this exemplary case shows the ways that CSR often operates to deflect ethical critiques, consolidate brand loyalty and corporate profits, and defuse political struggles around consumption. By doing so, we suggest that CSR forms part of a complex strategy deployed to legitimize particular brands and commodities. In this way CSR can be seen as playing an important role in the ideological makeup of contemporary consumer capitalism. </jats:p

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr

Patients with schizophrenia show deficits of working memory maintenance components in circuit-specific tasks

Working memory (WM) deficits are a neuropsychological core finding in patients with schizophrenia and also supposed to be a potential endophenotype of schizophrenia. Yet, there is a large heterogeneity between different WM tasks which is partly due to the lack of process specificity of the tasks applied. Therefore, we investigated WM functioning in patients with schizophrenia using process- and circuit-specific tasks. Thirty-one patients with schizophrenia and 47 controls were tested with respect to different aspects of verbal and visuospatial working memory using modified Sternberg paradigms in a computer-based behavioural experiment. Total group analysis revealed significant impairment of patients with schizophrenia in each of the tested WM components. Furthermore, we were able to identify subgroups of patients showing different patterns of selective deficits. Patients with schizophrenia exhibit specific and, in part, selective WM deficits with indirect but conclusive evidence of dysfunctions of the underlying neural networks. These deficits are present in tasks requiring only maintenance of verbal or visuospatial information. In contrast to a seemingly global working memory deficit, individual analysis revealed differential patterns of working memory impairments in patients with schizophrenia

Type D personality is associated with increased metabolic syndrome prevalence and an unhealthy lifestyle in a cross-sectional Dutch community sample

<p>Abstract</p> <p>Background</p> <p>People with Type D-Distressed-personality have a general tendency towards increased negative affectivity (NA), while at the same time inhibiting these emotions in social situations (SI). Type D personality is associated with an increased risk of adverse outcomes in patients with cardiovascular disease. Whether Type D personality is a cardiovascular risk factor in healthy populations remains to be investigated. In the present study, the relations between Type D personality and classical cardiovascular risk factors, i.e. metabolic syndrome and lifestyle were investigated in a Dutch community sample.</p> <p>Methods</p> <p>In a cross-sectional study 1592 participants were included, aged 20-80 years. Metabolic syndrome was defined by self-report, following the International Diabetes Federation-IDF-guidelines including an increased waist circumference, dyslipidemia, hypertension, and diabetes. In addition lifestyle factors smoking, alcohol use, exercise and dietary habits were examined. Metabolic syndrome prevalence was stratified by Type D personality (a high score on both NA and SI), lifestyle and confounders age, gender, having a partner, higher education level, cardiac history, family history of cardiovascular disease.</p> <p>Results</p> <p>Metabolic syndrome was more prevalent in persons with a Type D personality (13% vs. 6%). Persons with Type D personality made poorer lifestyle choices, adhered less to the physical activity norm (OR = 1.5, 95%CI = 1.1-2.0, <it>p </it>= .02), had a less varied diet (OR = 0.50, 95%CI = 0.40-0.70, <it>p </it>< .0005), and were less likely to restrict their fat intake (OR = 0.70, 95%CI = 0.50-0.90, <it>p </it>= .01). Type D personality was related to a twofold increased risk of metabolic syndrome (OR = 2.2, 95%CI = 1.2-4.0, <it>p </it>= .011), independent of lifestyle factors and confounders.</p> <p>Conclusions</p> <p>Type D personality is related to an increased prevalence of metabolic syndrome and unhealthy lifestyle, which suggests both behavioral and biological vulnerability for development of cardiovascular disorders and diabetes.</p

Deep-Inelastic Inclusive ep Scattering at Low x and a Determination of alpha_s

A precise measurement of the inclusive deep-inelastic e^+p scattering cross section is reported in the kinematic range 1.5<= Q^2 <=150 GeV^2 and 3*10^(-5)<= x <=0.2. The data were recorded with the H1 detector at HERA in 1996 and 1997, and correspond to an integrated luminosity of 20 pb^(-1). The double differential cross section, from which the proton structure function F_2(x,Q^2) and the longitudinal structure function F_L(x,Q^2) are extracted, is measured with typically 1% statistical and 3% systematic uncertainties. The measured partial derivative (dF_2(x,Q^2)/dln Q^2)_x is observed to rise continuously towards small x for fixed Q^2. The cross section data are combined with published H1 measurements at high Q^2 for a next-to-leading order DGLAP QCD analysis.The H1 data determine the gluon momentum distribution in the range 3*10^(-4)<= x <=0.1 to within an experimental accuracy of about 3% for Q^2 =20 GeV^2. A fit of the H1 measurements and the mu p data of the BCDMS collaboration allows the strong coupling constant alpha_s and the gluon distribution to be simultaneously determined. A value of alpha _s(M_Z^2)=0.1150+-0.0017 (exp) +0.0009-0.0005 (model) is obtained in NLO, with an additional theoretical uncertainty of about +-0.005, mainly due to the uncertainty of the renormalisation scale.Comment: 68 pages, 24 figures and 18 table