Extra-hematopoietic effects of erythropoietin

Erythropoietin (Epo) has a long-lasting history as the hormon that allows production of red blood cells. It is now well established that, besides erythropoiesis, Epo has the ability to sustain proliferation of myeloid lineages. More recently, extra-haematological roles have been described for Epo. Its receptor, EpoR, has been detected at the membrane of several neoplastic and normal cell types from the central nervous system and other non haematological cell lines. Whereas Epo-EpoR have been detected several years ago in some extra-haematological normal lineages, their role has long been underestimated whereas they may be crucial for proliferation and survival. Consequently, efforts have recently increased to identify the precise role of Epo-EpoR in a variety of cell types. This allowed identification of physiologically relevant targets that led to original therapeutic strategies.     

Separation and quantification of ropinirole and some impurities using capillary liquid chromatography.

Ropinirole, 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one, is a potent anti-Parkinson's disease drug developed by SmithKline Beecham Pharmaceuticals. Capillary liquid chromatography (CLC) was used for the separation and quantification of ropinirole and its five related impurities, potentially formed during its synthesis. A simultaneous optimization of three mobile phase parameters, i.e., pH, buffer concentration and acetonitrile content was performed employing an experimental design approach which proved a powerful tool in method development. The retention factors of the investigated substances in different mobile phases were determined. Baseline resolution of the six substances on a C18 reversed stationary phase was attained using a mobile phase with an optimized composition [acetonitrile-8.7 mM 2-(N-morpholino)ethanesulfonic acid adjusted to pH 6.0 (55:45, v/v)]. It was shown that CLC, operated in the isocratic mode under the mobile phase flow-rate of 4 microl/min, can determine the level of these impurities, down to a level of 0.06% of the main component within 25 min.     

Adolescent physical performance and adult physical activity in Flemish males

Limited information is available about the associations between adolescent fitness levels and adult physical activity. In the present study, these associations are investigated using different indicators of physical activity. It is hypothesized that both health‐ and performance‐related fitness characteristics, observed during the adolescent period, contribute equally to the explained variance in adult physical activity levels. Subjects were 109 Flemish males followed over a period of 27 years from 13 to 40 years of age in the Leuven Longitudinal Study on Lifestyle Fitness and Health. Performance and health‐related fitness characteristics were observed during the growth period and at 40 years of age. The Work Index, Leisure Time Index, and Sport Index of the Baecke questionnaire were used as indicators of physical activity together with triaxial accelerometry. Multiple regression and discriminant analyses contrasting extreme quintiles of activity groupings were used to analyse the associations. Only the Baecke Sport Index showed consistent significant associations (R² = 0.03 to R² = 0.23) with adolescent fitness levels observed at 13, 15, and 18 years. When upper and lower quintiles were contrasted, fitness characteristics observed at the three age levels during adolescence were significantly different for each of the three indices of the Baecke questionnaire at 40 years of age. Lowest associations (R² = 0.09 to R² = 0.17) were found for the Work Index, followed by the Leisure Time Index (R² = 0.12 to R² = 0.28) and Sport Index (R² = 0.25 to R² = 0.43). Highest associations were evident for the 18‐ to 40‐year interval. Performance‐ and health‐related fitness characteristics explain equally well the variance in physical activity indicators. Am. J. Hum. Biol. 13:173–179, 2001. © 2001 Wiley‐Liss, Inc.     

Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo

Results from retrospective studies on the relationship between cytochrome P450 (P450) 2B6 (CYP2B6) genotype and cyclophosphamide (CY) efficacy and toxicity in adult cancer patients have been conflicting. We evaluated this relationship in children, who have faster CY clearance and receive different CY-based regimens than adults. These factors may influence the P450s metabolizing CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Therefore, we sought to characterize the in vitro and in vivo roles of hepatic CYP2B6 and its main allelic variants in 4HCY formation. CYP2B6 is the major isozyme responsible for 4HCY formation in recombinant P450 Supersomes. In human liver microsomes (HLM), 4HCY formation correlated with known phenotypic markers of CYP2B6 activity, specifically formation of (S)-2-ethyl-1,5-dimethyl-3,3-diphenyl pyrrolidine and hydroxybupropion. However, in HLM, CYP3A4/5 also contributes to 4HCY formation at the CY concentrations similar to plasma concentrations achieved in children (0.1 mM). 4HCY formation was not associated with CYP2B6 genotype at low (0.1 mM) or high (1 mM) CY concentrations potentially because CYP3A4/5 and other isozymes also form 4HCY. To remove this confounder, 4HCY formation was evaluated in recombinant CYP2B6 enzymes, which demonstrated that 4HCY formation was lower for CYP2B6.4 and CYP2B6.5 compared with CYP2B6.1. In vivo, CYP2B6 genotype was not directly related to CY clearance or ratio of 4HCY/CY areas under the curve in 51 children receiving CY-based regimens. Concomitant chemotherapy agents did not influence 4HCY formation in vitro. We conclude that CYP2B6 genotype is not consistently related to 4HCY formation in vitro or in vivo.     

Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock

Purpose

Septic shock induces a decrease in dendritic cells (DCs) that may contribute to sepsis-induced immunosuppression. We analyzed the time course of circulating DCs in patients with septic shock and its relation to susceptibility to intensive care unit (ICU)-acquired infections.

Methods

We enrolled adult patients with septic shock (n?=?43), non-septic shock (n?=?29), and with sepsis without organ dysfunction (n?=?16). Healthy controls (n?=?16) served as reference. Blood samples were drawn on the day of shock (day 1), then after 3 and 7?days. Myeloid (mDC) and plasmacytoid (pDC) DCs were counted by flow cytometry. Cell surface HLA-DR expression was analyzed in both DC subsets.

Results

At day 1, median mDC and pDC counts were dramatically lower in septic shock patients as compared to healthy controls (respectively, 835?mDCs and 178?pDCs/ml vs. 19,342?mDCs and 6,169?pDCs/ml; P?P?Conclusion Septic shock is associated with profound and sustained depletion of circulating DCs. The persistence of low mDC counts is associated with the development of ICU-acquired infections, suggesting that DC depletion is a functional feature of sepsis-induced immunosuppression.     

Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis

Verbeek MM, Notting EA, Faas B, Claessens‐Linskens R, Jongen PJH. Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis.
Acta Neurol Scand: 2010: 121: 309–314.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To investigate chitotriosidase (CTTS) activity in serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS) patients in relation to disease course and CSF markers for immune activation or inflammation. Materials and methods – We studied 80 patients with relapsing–remitting MS (RRMS), 24 with secondary progressive MS (SPMS), 20 with primary progressive MS (PPMS) and 29 patients with other neurological disorders (OND). We measured CTTS activity and studied the correlation with CSF mononuclear cell count (MNC) and intrathecal IgG production. Results – CTTS activity was significantly higher in CSF, but not in serum, from the total MS group compared with OND and controls. In RRMS and SPMS CTTS, index was increased compared with controls (RRMS, 0.10 ± 0.21; SPMS, 0.10 ± 0.15; controls, 0.021 ± 0.020), but not in PPMS (0.061 ± 0.052). CTTS index was higher in MS patients with elevated MNC or CSF‐restricted oligoclonal IgG bands than in MS patients without these CSF findings. Conclusions – CTTS index is elevated in RRMS and SPMS. The CTTS index is related to CSF markers of inflammation or immune activation.     

Can C-reactive protein,procalcitonin and mid-regional pro-atrial natriuretic peptide measurements guide choice of in-patient or out-patient care in acute pyelonephritis? Biomarkers In Sepsis (BIS) multicentre study

Whereas C-reactive protein (CRP), procalcitonin (PCT) and mid-regional pro-atrial natriuretic peptide (ANP) may be of use at the bedside in the management of adult patients with infectious disorders, their usefulness has not been established in the setting of acute pyelonephritis. To assess the effectiveness of CRP, PCT and ANP measurements in guiding emergency physicians' decisions whether to admit to hospital patients with acute pyelonephritis, we conducted a multicentre, prospective, observational study in 12 emergency departments in France; 582 consecutive patients were included. The reference standard for admission was defined by experts' advice combined with necessity of admission or death during the 28-day follow-up. Baseline CRP, PCT and ANP were measured and their accuracy in identifying the necessity of admission was analysed using area under curves (AUC) of receiver–operating characteristic (ROC) plots. According to the reference standard, 126 (22%) patients required admission. ANP (AUC 0.75, 95% CI 0.69–0.80) and PCT (AUC 0.75, 95% CI 0.71–0.80) more accurately predicted this than did CRP (AUC 0.69, 95% CI 0.64–0.74). The -positive and negative likelihood ratios for each biomarker remained clinically irrelevant whatever the threshold. Our results did not support the use of these markers to help physicians in deciding about admission of patients experiencing acute pyelonephritis in daily practice.     

A growth curve to model changes in sport participation in adolescent boys

The aims of this study are twofold: (1) to present the latent growth model, its strategy and usefulness in modelling sport participation over a 6‐year period in youngsters (2) and to study the impact of biological maturation in sport participation changes. A standardized sport participation questionnaire using h/week/year as the unit of analysis was applied to 588 Belgium boys 13–18 years of age followed longitudinally for 6 years. Skeletal age was used to estimate biological maturation. Growth curve modelling with robust estimation was used. Sport participation changes showed a curvilinear trend: baseline values (3.18±0.13 h/week/year), a linear trend that indicates the rate of change (0.70±0.11) and a quadratic trend indicating deceleration, i.e. a change in the rate of change (?0.07±0.02) were all statistically significant (P<0.05), as well as inter‐individual differences in these three parameters. Up to 16.8 years, the rate of sports participation increased 0.70 h/week/year and then declined. Biological maturation did not show any association with adolescent changes in sport participation.     

Food intake and inflammation in European children: the IDEFICS study

Purpose

This cross-sectional study assesses the relationship between consumption frequencies of food items and high-sensitivity C-reactive protein (hs-CRP) in European children.

Methods

Out of the baseline sample (N = 16.228) of the IDEFICS study, 6.403 children (1.315 boys aged 2 to <6, 1.908 boys aged 6 to <10, 1.204 girls aged 2 to <6 and 1.976 girls aged 6 to <10 years) had hs-CRP measured and the Children’s Eating Habits Questionnaire filled, including a food frequency questionnaire. Logistic regression adjusted for body mass index z-score, education of the mother, breast-feeding and self-reported hours of physical activity in a sport club per week was conducted.

Results

Mean frequency intake of raw vegetable was lower in boys (p = 0.022 in young and p = 0.020 in old) and older girls (p = 0.026) with high hs-CRP concentration, while in younger girls (p = 0.008) the same occurred with the cooked vegetables. The probability of having higher hs-CRP concentration was significantly associated with having low consumption frequency of vegetables (p = 0.004 in older boys, raw vegetables; and p = 0.0032 in younger girls, cooked vegetables). Also, honey/jam intake decreased the probability of having higher concentration of hs-CRP, whereas soft drinks with sugar, mayonnaise and cereals milled increased this probability.

Conclusions

Out of all food items associated with hs-CRP, frequency intake of vegetables presented more associations across all the analysis. Findings suggest that a high-frequency intake of vegetables is inversely related to an inflammatory status in children. More studies are needed to assess the association between diet and inflammation.