Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients

Aim To explore relationships between sirolimus dosing, concentration and clinical outcomes. Methods Data were collected from 25 kidney transplant recipients (14 M/11 F), median 278 days after transplantation. Outcomes of interest were white blood cell (WBC) count, platelet (PLT) count, and haematocrit (HCT). A naive pooled data analysis was performed with outcomes dichotomized (Mann-Whitney U-tests). Results Several patients experienced at least one episode when WBC (n = 9), PLT (n = 12), or HCT (n = 21) fell below the lower limits of the normal range. WBC and HCT were significantly lower (P < 0.05) when sirolimus dose was greater than 10 mg day(-1), and sirolimus concentration greater than 12 mu g l(-1). No relationship was shown for PLT and dichotomized sirolimus dose or concentration. Conclusions Given this relationship between sirolimus concentration and effect, linked population pharmacokinetic-pharmacodynamic modelling using data from more renal transplant recipients should now be used to quantify the time course of these relationships to optimize dosing and minimize risk of these adverse outcomes.

Co-expression of SOX9 and SOX10 during melanocytic differentiation in vitro

Investigations into pigment cell biology have relied on the ability to culture both murine and human melanocytes, numerous melanoma cell lines and more recently, murine and human melanoblasts. Melanoblast culture requires medium supplemented with a range of growth factors including Stem Cell Factor, Endothelin-3 and Fibroblast Growth Factor-2, withdrawal of which causes the cells to differentiate into melanocytes. Using the human melanoblast culture system, we have now examined the expression and/or DNA binding activity of several transcription factors implicated in melanocytic development and differentiation. Of these, the POU domain factor BRN2 and the SOX family member SOX10 are both highly expressed in unpigmented melanocyte precursors but are down-regulated upon differentiation. In contrast, the expression levels of the previously described MITF and PAX3 transcription factors remain relatively constant during the melanoblast-melanocyte transition. Moreover, BRN2 ablated melanoma cells lack expression of SOX10 and MITF but retain PAX3. A novel finding implicates a second SOX protein, SOX9, as a potential melanogenic transcriptional regulator, as its expression level is increased following the down-regulation of BRN2 and SOX10 in differentiated melanoblasts. Our results suggest that a complex network of transcription factor interactions requiring proper temporal coordination is necessary for acquisition and maintenance of the melanocytic phenotype. (c) 2005 Elsevier Inc. All rights reserved.

Relationships of sauries and needlefishes (Teleostei : Scomberesocoidea) to the internally fertilizing halfbeaks (Zenarchopteridae) based on the pharyngeal jaw apparatus

The 40 life history, myological, and osteological characters that Tibbetts (1992) used in his study of the hemiramphids are evaluated for both saury genera (Cololabis and Scomberesox) to determine if the Scomberesocidae are more closely related to the Zenarchopteridae, to the needlefishes (Belonidae), or to the halfbeaks (Hemiramphidae) and flyingfishes (Exocoetidae). Data were analyzed using PAUP*, and eight equally parsimonious trees were found (70 steps, CI 0.814, RI 0.938). This analysis indicates that sauries are most closely related to needlefishes, supporting the historical concept of the superfamily Scomberesocoidea as a monophyletic assemblage. A caudal displacement of the origin of the retractor dorsalis muscle is a tentative additional synapomorphy for all four saury species. Zenarchopteridae is strongly supported as a valid family sister to the Scomberesocoidea (decay index = 19, bootstrap = 100). Resolution of the internal structure of the Belonidae and the Hemiramphidae requires the identification of additional characters and examination of a greater number of taxa.

Differentiation between and within groups: The influence of individualist and collectivist group norms

The power of individualist and collectivist group norms to influence intergroup and inter-individual differentiation was examined in three studies. Study I revealed that intergroup differentiation was lower when group norms prescribed individualism than when they prescribed collectivism. However inter-individual differentiation was higher when group norms endorsed individualism than when they promoted collectivism. In Studies 2 and 3 we found evidence for the moderating effect of group salience on the relationship between norms and differentiation. Specifically, the effect that individualist group norms reduced intergroup differentiation but enhanced inter-individual differentiation was more pronounced when group salience was high rather than low. This finding demonstrates that conformity to a group norm prescribing individualism influences the manner in which positive differentiation is expressed. The discussion focuses on the caveats of introducing individualist group norms when attempting to reduce intergroup differentiation. Copyright (c) 2006 John Wiley & Sons, Ltd.