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

Illness management and recovery (IMR) in Danish community mental health centres

<p>Abstract</p> <p>Background</p> <p>Schizophrenia and bipolar disorder are severe mental illnesses that can have a significant disabling impact on the lives of people. Psychosocial interventions that stress hope and recovery as a part of a multi-dimensional approach are possibly indicated to support people with severe mental illness in facilitating recovery. Illness Management and Recovery (IMR) is a curriculum-based psychosocial intervention designed as structured program with a recovery-oriented approach. The aim of IMR is to rehabilitate people with severe mental illnesses by helping them acquire knowledge and skills in managing their illness and achieve personal recovery goals. Previous randomised clinical trials indicate that IMR can be implemented with a good effect and a high fidelity though further trials are crucial to demonstrate the potential effectiveness of IMR.</p> <p>Methods/Design</p> <p>The trial design is a randomised, assessor-blinded, multi-centre, clinical trial of the IMR program compared with treatment as usual for 200 participants diagnosed with schizophrenia or bipolar disorder under the care of two community mental health centres in the Capital Region of Denmark. The primary outcome is level of functioning at the end of treatment. The secondary outcomes are disease symptoms; use of alcohol/drugs; individual meaning of recovery; hope; hospital admissions and out-patient psychiatric treatment at the end of treatment and the abovementioned and level of functioning at follow-up 21 months after baseline.</p> <p>Discussion</p> <p>If the results of this trial show IMR to be effective these positive results will strengthen the evidence of IMR as an effective comprehensive psychosocial intervention with a recovery-oriented approach for people with severe mental illness. This will have significant implications for the treatment and recovery of people with severe mental illness.</p> <p>Trial registration</p> <p>Registration number <a href="http://www.clinicaltrials.gov/ct2/show/NCT01361698">NCT01361698</a>.</p

Global Assessment of Functioning (GAF): properties and frontier of current knowledge

ABSTRACT: BACKGROUND: Global Assessment of Functioning (GAF) is well known internationally and widely used for scoring the severity of illness in psychiatry. Problems with GAF show a need for its further development (for example validity and reliability problems). The aim of the present study was to identify gaps in current knowledge about properties of GAF that are of interest for further development. Properties of GAF are defined as characteristic traits or attributes that serve to define GAF (or may have a role to define a future updated GAF). METHODS: A thorough literature search was conducted. RESULTS: A number of gaps in knowledge about the properties of GAF were identified: for example, the current GAF has a continuous scale, but is a continuous or categorical scale better? Scoring is not performed by setting a mark directly on a visual scale, but could this improve scoring? Would new anchor points, including key words and examples, improve GAF (anchor points for symptoms, functioning, positive mental health, prognosis, improvement of generic properties, exclusion criteria for scoring in 10-point intervals, and anchor points at the endpoints of the scale)? Is a change in the number of anchor points and their distribution over the total scale important? Could better instructions for scoring within 10-point intervals improve scoring? Internationally, both single and dual scales for GAF are used, but what is the advantage of having separate symptom and functioning scales? Symptom (GAF-S) and functioning (GAF-F) scales should score different dimensions and still be correlated, but what is the best combination of definitions for GAF-S and GAF-F? For GAF with more than two scales there is limited empirical testing, but what is gained or lost by using more than two scales? CONCLUSIONS: In the history of GAF, its basic properties have undergone limited changes. Problems with GAF may, in part, be due to lack of a research programme testing the effects of different changes in basic properties. Given the widespread use, research-based development of GAF has not been especially strong. Further research could improve GAF

Individual time within target range in patients treated with vitamin K antagonists:main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism

The efficacy and safety of vitamin K antagonists (VKA) are related to the actual level of anticoagulation (given as the international normalized ratio, INR). It is often difficult to maintain an optimal INR over time. We assessed the clinical impact of the individual time spent within INR target range (ITTR) in 2304 consecutive patients with venous thromboembolism. Annual incidences of recurrent thromboembolism and major bleeding were 6.2% and 2.8% respectively. The relative risk (RR) of thromboembolism was 4.5 [95% confidence interval (CI) 3.1-6.6, P &lt;0.001] at INR &lt;2.0, for major bleeding it was 6.4 (2.5-16.1, P &lt;0.001) at INR &gt; 5.0, compared with INR 2.0-3.0. Patients with ITTR &lt;45% were at higher risk than those with ITTR &gt; 65% (RR 2.8, 1.9-4.3, P &lt;0.001), while no difference was demonstrated comparing ITTR 45-65% and ITTR &gt; 65% (RR 1.2, 0.7-1.8, P = 0.54). Annual incidences of recurrent thromboembolism were 16.0%, 4.9% and 4.6% at ITTR &lt;45%, 45-60% and &gt;65% respectively. For major bleeding these were 8.7%, 2.1% and 1.9% respectively. ITTR &lt;37% during the first 30 treatment days was highly predictive for the total treatment time ITTR &lt;45% (RR 24.2, 13.5-43.1, P &lt;0.001). In conclusion, ITTR can be used to identify patients on VKA at risk of recurrent thromboembolism or major bleeding. Since the 30-d ITTR is highly predictive for total treatment ITTR, these patients can be identified soon after start of treatment.</p