Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4β-hydroxycholesterol

International audienc

NK-cell and T-cell functions in patients with breast cancer: effects of surgery and adjuvant chemo- and radiotherapy

Breast cancer is globally the most common malignancy in women. Her2-targeted monoclonal antibodies are established treatment modalities, and vaccines are in late-stage clinical testing in patients with breast cancer and known to promote tumour-killing through mechanisms like antibody-dependent cellular cytotoxicity. It is therefore increasingly important to study immunological consequences of conventional treatment strategies. In this study, functional tests and four-colour flow cytometry were used to detect natural killer (NK)-cell functions and receptors as well as T-cell signal transduction molecules and intracellular cytokines in preoperative breast cancer patients, and patients who had received adjuvant radiotherapy or adjuvant combined chemo-radiotherapy as well as in age-matched healthy controls. The absolute number of NK cells, the density of NK receptors as well as in vitro quantitation of functional NK cytotoxicity were significantly higher in preoperative patients than the post-treatments group and controls. A similar pattern was seen with regard to T-cell signalling molecules, and preoperative patients produced significantly higher amounts of cytokines in NK and T cells compared to other groups. The results indicate that functions of NK and T cells are well preserved before surgery but decrease following adjuvant therapy, which may speak in favour of early rather than late use of immunotherapeutic agents such as trastuzumab that may depend on intact immune effector functions

Long-Term Follow-Up of Transsexual Persons Undergoing Sex Reassignment Surgery: Cohort Study in Sweden

CONTEXT: The treatment for transsexualism is sex reassignment, including hormonal treatment and surgery aimed at making the person's body as congruent with the opposite sex as possible. There is a dearth of long term, follow-up studies after sex reassignment. OBJECTIVE: To estimate mortality, morbidity, and criminal rate after surgical sex reassignment of transsexual persons. DESIGN: A population-based matched cohort study. SETTING: Sweden, 1973-2003. PARTICIPANTS: All 324 sex-reassigned persons (191 male-to-females, 133 female-to-males) in Sweden, 1973-2003. Random population controls (10:1) were matched by birth year and birth sex or reassigned (final) sex, respectively. MAIN OUTCOME MEASURES: Hazard ratios (HR) with 95% confidence intervals (CI) for mortality and psychiatric morbidity were obtained with Cox regression models, which were adjusted for immigrant status and psychiatric morbidity prior to sex reassignment (adjusted HR [aHR]). RESULTS: The overall mortality for sex-reassigned persons was higher during follow-up (aHR 2.8; 95% CI 1.8-4.3) than for controls of the same birth sex, particularly death from suicide (aHR 19.1; 95% CI 5.8-62.9). Sex-reassigned persons also had an increased risk for suicide attempts (aHR 4.9; 95% CI 2.9-8.5) and psychiatric inpatient care (aHR 2.8; 95% CI 2.0-3.9). Comparisons with controls matched on reassigned sex yielded similar results. Female-to-males, but not male-to-females, had a higher risk for criminal convictions than their respective birth sex controls. CONCLUSIONS: Persons with transsexualism, after sex reassignment, have considerably higher risks for mortality, suicidal behaviour, and psychiatric morbidity than the general population. Our findings suggest that sex reassignment, although alleviating gender dysphoria, may not suffice as treatment for transsexualism, and should inspire improved psychiatric and somatic care after sex reassignment for this patient group

Pharmacokinetic studies on cladribine

The aims of the present study were to delineate the pharmacokinetics, in plasma and leukaemia cells, of cladribine (M), and to describe factors influencing the outcome of administration of CdA in order to individualize and optimize treatment. CdA is a nucleoside analogue with a cytotoxic activity in low-grade lymphoproliferative disorders and childhood acute myelogenous leukaemia. In addition, it has an immunomodulating effect used in multiple sclerosis. CdA is unstable at low pH and is deglycosylated by bacterial nucleoside phosphorylases. CdA can also be cleaved, in an enzymatic reaction in the presence of the hepatic enzyme methylthioadenosine phosphorylase, to the main metabolite 2chloroadenine (CAde). A more stable fluorinated analogue of CdA has been developed, 2-chloro-2'-arabio-fluoro-2'- deoxyadenosine (CAFdA). A reversed-phase high-performance liquid chromatographic method was developed for analyses of CdA, CAde and CAFdA. To minimize degradation before analysis, samples should be kept cold and not stored for more than 10 weeks. In a study Of 17 patients with leukaemia, we found large interpatient variability in both pharmacokinetic variables and a four-fold difference in activating enzyme activity. No clear correlations were seen between the plasma levels of CdA and the intracellular concentration of the active triphosphate, or to the response of treatment. The half-life was to some degree shorter for intracellular CdA-phosphates compared to CdA in plasma. In another study including 53 patients, we found no correlation between the the activity of the activating enzymes and the antiproliferative activity of CdA or the intracellular nucleotide levels of CdA in vitro. However, there was a large interindividual variability in enzyme activity and cytotoxicity. In a retrospective study consisting of 163 patients with different diagnoses, receiving different doses of CdA, administered by four different routes, using different treatment schedules, leaving different numbers of blood samples at different times, we used non- linear mixed effect modelling for the pharmaco-kinetic evaluation. For patients in the population with a mean weight of 73 kg, the clearance was 35 L/h with interindividual variability of 49% and half-life was estimated to be 17 hours. The oral bioavailability was 33% but the vari-ability after oral treatment was not increased compared with the variability after intravenous infusion. Individualized dosing on bases of BSA or weight is in this study not superior to administer all patients a fixed dose. The metabolite CAde has a lower cytotoxic effect than CdA, but may contribute to the cytotoxicity after oral administration, since 5 times more CAde was formed after oral treatment than after iv infusion (n=31 patients) and protein-binding of CAde is twice that of CdA. In conclusion, CdA can, by preference, be orally administered if the dose is adjusted for bioavailability and cytotoxicity of the metabolite, CAde

[Careful medical history taking is worthwhile in child sleep disorders]

Sleeping disturbances are common in children and adolescents and in rare cases signal underlying disease. Complete history and diagnosis are mandatory for treatment. The basis for pharmacologic treatment is unsatisfactory but phenotiazides and benzodiazepines should not be used because of lack of documented effects and potentially serious side effects. Melatonin may be used in selected cases