Central diabetes insipidus: beware of Langerhans cell histiocytosis!

Langerhans cell histiocytosis (LCH) is a rare disorder, characterised by a monoclonal proliferation of aberrant histiocytes that accumulate in and infiltrate into different organs. When the hypothalamic-pituitary axis is involved, central diabetes insipidus (CDI) can be its first manifestation. Three cases of LCH with central diabetes insipidus were retrospectively analyzed: Case 1 is a 41-year old female presenting with polyuria and polydipsia. Diabetes insipidus was diagnosed and treated with desmopressin. MRI pituitary showed hypophysitis. Subsequently, she developed bone lesions and a biopsy demonstrated LCH. Case 2 is a 51-year old female presenting in 2009 with polyuria and polydipsia. Diabetes insipidus was diagnosed and treated with desmopressin. MRI pituitary revealed hypophysitis. LCH was suspected because of known pulmonary histiocytosis. Coexisting bone lesions were biopsied and confirmed LCH. Case 3 is a 44-year old female presenting with diabetes insipidus. She was treated with desmopressin as well. MRI of the pituitary gland showed impressive thickening of the infundibulum. A few months later, she developed skin lesions and a biopsy revealed LCH. Conclusively, LCH is a rare, elusive and probably underdiagnosed disease with a broad disease spectrum. Due to infiltration of the hypothalamic-pituitary axis, CDI can be the first manifestation, even before LCH is diagnosed. Therefore, LCH should be considered in the diagnostic workup of CDI.

Economic evaluation of S. boulardii CNCM I-745 for prevention of antibioticassociated diarrhoea in hospitalized patients.

Interest in administration of probiotics to prevent antibiotic-associated diarrhoea (AAD) in hospitalized patients is increasing. We determined the cost of antibiotic-associated diarrhoea in hospital settings for non-complicated and Clostridium difficile (C.diff) complicated AAD, and performed a health-economic analysis of AAD prevention with S. boulardii CNCM I-745 (S. boulardii) from data collected in 1 university and 3 regional hospitals in Flanders. Using a decision tree analytic model, costs and effects of S. boulardii for AAD prevention are calculated. Incremental costs due to AAD, including increased length of hospitalization, were calculated using bottom-up and top-down costing approaches from a hospital, healthcare payer (HCP) and societal perspective. Model robustness was tested using sensitivity analyses. Additional costs per hospitalized patient range from € 277.4 (hospital) to € 2,150.3 (societal) for non-complicated and from € 588.8 (hospital) to € 2,239.1 (societal) for C. diff. complicated AAD. Using S. boulardii as AAD prevention results in cost savings between € 50.3 (bottom-up) and € 28.1 (topdown) per patient treated with antibiotics from the HCP perspective; and € 95.2 and € 14.7 per patient from the societal and hospital perspectives. Our analysis shows the potential for using S. boulardii as AAD prophylactic treatment in hospitalized patients. Based on 831,655 hospitalizations with antibiotic administration in 2014 and € 50.3 cost saving per patient on antibiotics, generalized use of S. boulardii could result in total annual savings up to € 41.8 million for the Belgian HCP.

Estradiol and weight are covariates of paracetamol clearance in young women.

AIM: Paracetamol clearance differs between pregnant and non-pregnant women and between women with or without specific oral contraceptives (OCs). However, an association between female sex hormones and paracetamol clearance has never been explored. METHODS: In total, 49 women at delivery, 8 female control subjects without OC use, historical data of 14 women taking OCs, and 15 postpartum observations with and without OCs were pooled to explore covariates of paracetamol clearance. All received a single intravenous 2-gram paracetamol dose, and blood samples were collected up to 6 h after dosing. High-performance liquid chromatography was used to quantify paracetamol. The area under the curve to time infinity (AUC0-∞) was determined and clearance (l/h·m(2)) was calculated by dose/ AUC0-∞. In addition, estradiol and progesterone were quantified by ELISA with electro-chemiluminescence. RESULTS: Median paracetamol clearance at delivery was significantly higher when compared to postpartum or non-pregnant women (11.9 vs. 6.42 and 8.4 l/h·m(2), at least p < 0.05), while an association between paracetamol clearance and estradiol was observed (R = 0.494, p < 0.0001). In non-pregnant subjects, there was no impact of OC exposure on paracetamol clearance. Multiple regression revealed a linear association (Radj = 0.41, p < 0.001) between paracetamol clearance and weight (p = 0.0462) and estradiol (p < 0.0001). CONCLUSION: Estradiol and weight in part explain the variation in paracetamol clearance in young women.

Development of an experimental model to study trigeminal nerve-mediated vasodilation on the human forehead.

BACKGROUND: During migraine, trigeminal sensory nerve terminals release calcitonin gene-related peptide (CGRP), inducing nociception and vasodilation. Applied on the skin, capsaicin activates the transient receptor potential vanilloid type 1 (TRPV1) channel and releases CGRP from sensory nerve terminals, thus increasing dermal blood flow (DBF). Using capsaicin application and electrical stimulation of the forehead skin, a trigeminal nerve-innervated dermatome, we aimed to develop a model to measure trigeminal nerve-mediated vasodilation in humans. METHODS: Using laser Doppler imaging, forehead DBF responses to application of capsaicin (0.06 mg/ml and 6.0 mg/ml) and saline, with and without iontophoresis, were studied in healthy subjects. The within-subject coefficient of variation (WCV) of repeated DBF measurements was calculated to assess reproducibility. RESULTS: Maximal DBF responses to 6.0 mg/ml capsaicin with and without iontophoresis did not differ (Emax 459 ± 32 and 424 ± 32 arbitrary units (a.u.), WCV 6 ± 4%). In contrast, DBF responses to 0.06 mg/ml capsaicin were significantly larger with than without iontophoresis (Emax 307 ± 60 versus 187 ± 21 a.u., WCV 21 ± 13%). Saline with iontophoresis significantly increased DBF (Emax: 245 ± 26 a.u, WCV 11 ± 8%), while saline application without iontophoresis did not affect DBF. CONCLUSION: Topical application of capsaicin and electrical stimulation induce reproducible forehead DBF increases and therefore are suitable to study trigeminal nerve-mediated vasodilation in humans.

Determining carotid artery pressure from scaled diameter waveforms: comparison and validation of calibration techniques in 2026 subjects.

Calibrated diameter distension waveforms could provide an alternative for local arterial pressure assessment more widely applicable than applanation tonometry. We compared linearly and exponentially calibrated carotid diameter waveforms to tonometry readings. Local carotid pressures measured by tonometry and diameter waveforms measured by ultrasound were obtained in 2026 subjects participating in the Asklepios study protocol. Diameter waveforms were calibrated using a linear and an exponential calibration scheme and compared to measured tonometry waveforms by examining the mean root-mean-squared error (RMSE), carotid systolic blood pressure (SBPcar) and augmentation index (AIx) of calibrated and measured pressures. Mean RMSE was 5.2(3.3) mmHg (mean(stdev)) for linear and 4.6(3.6) mmHg for exponential calibration. Linear calibration yielded an underestimation of SBPcar by 6.4(4.1) mmHg which was strongly correlated to values of brachial pulse pressure (PPbra) (R = 0.4, P < 0.05). Exponential calibration underestimated true SBPcar by 1.9(3.9) mmHg, independent of PPbra. AIx was overestimated by linear calibration by 1.9(10.1)%, the difference significantly increasing with increasing AIx (R = 0.25, P < 0.001) and by exponential calibration by 5.4(10.6)%, independently of the value of AIx. Properly calibrated diameter waveforms offer a viable alternative for local pressure estimation at the carotid artery. Compared to linear calibration, exponential calibration significantly improves the pressure estimation.

Both postnatal and postmenstrual age contribute to the interindividual variability in tramadol glucuronidation in neonates.

INTRODUCTION: Although of pharmacokinetic and -dynamic relevance, data on ontogeny of UDP-glucuronosyltransferase (UGT) activity in neonates are scant. We therefore wanted to assess the impact of both postnatal and postmenstrual age (PNA/PMA) on the interindividual variability of glucuronidation to overall tramadol urinary elimination in neonates. METHODS: O-demethyl tramadol (M1) and M1-glucuronide (M1G) were determined in 24 hour urine collections during continuous intravenous tramadol administration in neonates. Glucuronidation fraction (%) was calculated by the ratio of M1G to the sum of M1G and M1 free (M1total). Fractions (%) in early (

Nonlinear isochrones in murine left ventricular pressure-volume loops: how well does the time-varying elastance concept hold?

The linear time-varying elastance theory is frequently used to describe the change in ventricular stiffness during the cardiac cycle. The concept assumes that all isochrones (i.e., curves that connect pressure-volume data occurring at the same time) are linear and have a common volume intercept. Of specific interest is the steepest isochrone, the end-systolic pressure-volume relationship (ESPVR), of which the slope serves as an index for cardiac contractile function. Pressure-volume measurements, achieved with a combined pressure-conductance catheter in the left ventricle of 13 open-chest anesthetized mice, showed a marked curvilinearity of the isochrones. We therefore analyzed the shape of the isochrones by using six regression algorithms (two linear, two quadratic, and two logarithmic, each with a fixed or time-varying intercept) and discussed the consequences for the elastance concept. Our main observations were 1) the volume intercept varies considerably with time; 2) isochrones are equally well described by using quadratic or logarithmic regression; 3) linear regression with a fixed intercept shows poor correlation (R(2) < 0.75) during isovolumic relaxation and early filling; and 4) logarithmic regression is superior in estimating the fixed volume intercept of the ESPVR. In conclusion, the linear time-varying elastance fails to provide a sufficiently robust model to account for changes in pressure and volume during the cardiac cycle in the mouse ventricle. A new framework accounting for the nonlinear shape of the isochrones needs to be developed.

[Children from the GAZEL cohort: II--motive for contact with the medical-educational system by age and sex]. / Les enfants de la cohorte GAZEL: II--Motifs des contacts avec le système médico-éducatif, par âge et sexe.

An epidemiological survey of 2582 French children aged 4 to 16 has been conducted to assess patterns of service use in relation to psychological disturbances. Details on the design, sample, survey instruments, response rate, and 12-months prevalence rates of contacts with a range of different professionals were presented in a previous article. In this second article, the psychological motives leading to contact with family doctors, school-based professionals, speech and language therapists, and mental health specialists are analyzed. The age and gender effects are assessed for each motives. On the whole, consistent sex differences were found for the types of complaints presented by service users, with emotional symptoms being more frequent amongst girls, and behavioural, developmental and learning difficulties being more frequent amongst boys. Mental health specialists were attended for a variety of reasons. Family doctors were contacted for minor emotional difficulties. Because family doctors were consulted by a high proportion of children and adolescents of our sample, the role of this professionals in the detection and management of minor psychological morbidity is emphasized.

[Children of the GAZEL Cohort: I--Prevalence of contacts with the medico-educational system for psychological reasons, and associated factors]. / Les enfants de la Cohorte GAZEL: I--Prévalence des contacts avec le système médico-éducatif pour des motifs psychologiques, et facteurs associés.

An epidemiological survey of French children aged 4 to 16 was conducted in order to estimate the 12-months rates of service utilization for psychological reasons and to assess the factors associated with service use in this community sample. A large sample of 2582 children and adolescents was recruited from the families whose one parent was employed by the national electricity and gaz company (EDF-GDF). Of these employees, 20,000 have volunteered for a long-term prospective cohort study of their health and, since 1989, they have participated to annual surveys and additional ad hoc research programmes. Families with a child aged 4 to 16 in 1991 were selected. Only one child was selected in each family, and the sample was stratified by socio-economic status and family size according to census data. A survey questionnaire comprising a valid measure of child psychopathology (Child Behavior Checklist: CBCL) and an additional questionnaire including questions related to service use was used as a means of data collection. The response rate was 62.2% and factors associated with participation in the survey were analysed. The 12-months prevalence rate of contact for psychological motives were: 42.3% for general practitioners and family doctors, 7.8% for speech and language therapists, 9.5% for educational specialists, and 6.0% for mental health professionals. With the exception of general practitioners, rates of service contact were significantly higher for boys. Logistic regression analysis was used to identify separately factors associated with recent contact for each category of professionals. Results showed that, for all professionals, high scores on the CBCL measure was significantly associated with service use, the strongest association being found for mental health professionals. Family structure was also predictive of the latter, with higher rates of contacts for those children living in families whose parents are divorced, separated or widowed. Some differences for contacts with doctors were found according to the region; otherwise, no effects of socio-economic status, educational level of the parent, or other socio-economic indicators were found to predict service utilization. The implications for services are discussed.

In situ assay of acid sphingomyelinase and ceramidase based on LDL-mediated lysosomal targeting of ceramide-labeled sphingomyelin.

The activity of lysosomal sphingolipid hydrolases is usually estimated in vitro from complex assays on cell lysates under artificial conditions including the presence of detergents and substrate analogs. However, the measure of their effective activity in situ (i.e., in living cells) is necessary to understand the normal intracellular sphingolipid turnover. Moreover, their determination in cells from patients with genetic enzyme deficiencies represents a key parameter of the pathophysiology of sphingolipid storage disorders. In this report, we have developed a procedure for estimating the effective activity of lysosomal sphingomyelinase and ceramidase in situ. This procedure is based on the selective targeting to lysosomes of a natural substrate under physiological conditions of substrate influx. Epstein-Barr virus-transformed human lymphoid cells and human skin fibroblasts were incubated with purified human low density lipoproteins (LDL) containing [3H]ceramide-labeled sphingomyelin. Data demonstrate that this substrate is internalized through the apolipoprotein B/E receptor pathway and targeted to lysosomes. Lysosomal localization of the incorporated substrate was evidenced by ultrastructural autoradiography and subcellular fractionation as well as by metabolic studies in mutant cells. Short-term pulse-chase experiments with LDL-associated [3H]ceramide-labeled sphingomyelin allowed us to determine the effective activity of lysosomal sphingomyelinase and ceramidase in normal cells. Initial velocities of sphingomyelin and ceramide degradation were, respectively, estimated at 0.66 and 1.14 nmol.h-1.mg cell protein-1 in lymphoid cells, and 5.4 and 3 nmol.h-1.mg cell protein-1 in skin fibroblasts. The advantages and applications of these in situ studies are discussed.

Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis.

The nature of the signaling pathway(s) which initiate drug-triggered apoptosis remains largely unknown and is of fundamental importance in understanding cell death induced by chemotherapeutic agents. Here we show that in the leukemic cell lines U937 and HL-60, daunorubicin, at concentrations which trigger apoptosis, stimulated two distinct cycles of sphingomyelin hydrolysis (approximately 20% decrease at 1 microM) within 4-10 min and 60-75 min with concomitant ceramide generation. We demonstrate that the increase in ceramide levels, which precedes apoptosis, is mediated by a neutral sphingomyelinase and not by ceramide synthase. Indeed, potent ceramide synthase inhibitors such as fumonisin B1 did not affect daunorubicin-triggered sphingomyelin hydrolysis, ceramide generation or apoptosis. In conclusion, we provide evidence that daunorubicin-triggered apoptosis is mediated by a signaling pathway which is initiated by an early sphingomyelin-derived ceramide production.

Degradation of fluorescent and radiolabelled sphingomyelins in intact cells by a non-lysosomal pathway.

The aim of the present study was to investigate the role of the entitled neutral, sphingomyelinase in the non-lysosomal pathway of sphingomyelin degradation by intact cells (Spence et al. (1983) J. Biol. Chem. 258, 8595-8600; Levade et al. (1991) J. Biol. Chem. 266, 13519-13529). The uptake and degradation of sphingomyelin by intact living cells was studied using cell lines exhibiting a wide range of activity levels of acid, lysosomal and neutral sphingomyelinases as determined in vitro on cell homogenates by their respective standard assays. For this purpose, neuroblastoma, skin fibroblasts, lymphoid and leukemic cell lines, some of them derived from patients with Niemann-Pick disease (deficient in the acid, lysosomal sphingomyelinase) were incubated with radioactive, [oleoyl-3H]sphingomyelin or fluorescent, pyrene-sulfonylaminoundecanoyl-sphingomyelin. Either compound was taken up by a pathway which was not receptor-mediated and hydrolyzed by all intact cells, including those derived from Niemann-Pick disease patients. Moreover, their degradation by the intact cells was not inhibited by treatment with chloroquine, indicating hydrolysis by a non-lysosomal sphingomyelinase. The intracellular sphingomyelin degradation rates showed no correlation with the activity of the 'classical' neutral sphingomyelinase as determined in vitro. In particular, fibroblasts derived from Niemann-Pick patients lacking the lysosomal sphingomyelinase, and having no detectable in vitro activity of the 'classical' neutral sphingomyelinase, were able to degrade the exogenously supplied sphingomyelins. Indeed, in vitro these cells were shown to exhibit neutral, magnesium- and dithiothreitol-dependent sphingomyelinase activities, that might contribute to the non-lysosomal pathway for sphingomyelin degradation to ceramide in intact cells.