Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours

AIM

Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance.

METHODS

Forty-seven patients received GEM 1000–1250 mg m⁻² i.v. over 30 min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA.

RESULTS

Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration–time curve from time 0 to infinity (AUC(0,∞)) (r²= 0.77).

CONCLUSIONS

Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time.     

On the use of sample entropy to analyze human postural sway data

We analyze the irregularity of human postural sway data during quiet standing using the sample entropy (SampEn) algorithm. By considering recent methodological developments, we show that the SampEn parameter is able to characterize the irregularity of the center of pressure fluctuations through the analysis of the velocity variable. We present a practical method to select the input parameters of the SampEn algorithm. We show that the computed SampEn successfully discriminates two sensory conditions (eyes-open and eyes-closed) in a group of healthy young adults. We also perform surrogate data tests to investigate the nature of the underlying dynamics of our experimental data. Finally, the results of the proposed approach are compared to those obtained with the multiscale entropy algorithm.     

Psoas abscess: An unusual manifestation of Q fever

Q fever may lead to serious complications in chronically infected patients. We report two cases of psoas abscess due to Coxiella burnetii associated with lumbar osteomyelitis secondary to an aortic aneurysmal infection. Diagnosis was based on serology, and PCR detected C. burnetii DNA in an abscess sample.     

Characterizing the Dynamics of Postural Sway in Humans Using Smoothness and Regularity Measures

We investigate human postural sway velocity time series by computing two dynamical statistics quantifying the smoothness (the central tendency measure or CTM) and the regularity (the sample entropy or SampEn) of their underlying dynamics. The purpose of the study is to investigate the effect of aging and vision on the selected measures and to explore the nature of postural dynamics by performing surrogate data tests. A group of 14 young subjects was compared to a group of 11 older healthy subjects in two visual conditions: with eyes open (EO) and with eyes closed (EC). The results suggest that vision and age do not influence the two statistics of the velocity data in the same way. More specifically, the smoothness statistic is able to detect the aging effect. The regularity measure is sensitive to the visual feedback removal. In contrast with some findings in the literature, the results of the surrogate data tests indicate that the center of pressure velocity dynamics are stochastic and are not produced by a purely determinisitic behavior. Finally, we discuss some potential implications of our results in terms of postural control mechanisms.     

Early diagnosis of amoebic keratitis due to a mixed infection with <Emphasis Type="Italic">Acanthamoeba</Emphasis> and <Emphasis Type="Italic">Hartmannella</Emphasis>

A mixed keratitis due to Acanthamoeba and Hartmannella species is reported. The patient was a soft contact lens wearer. Early diagnosis was achieved by polymerase chain reaction and culture. The pathogenic potential of the isolated amoebae was proven using cytotoxicity assays. The reported case underlines the difficulties in identifying a corneal amoebic infection. In our case, the early diagnosis of a mixed infection allowed a proper antiamoebic treatment in an early stage of infection. This may have been the reason of a successful outcome after therapy.     

Antifungal Molecules Produced by a New Salt-Tolerant and Alkaliphilic Streptomyces sp. BS30 Isolated from an Arid Soil

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - A salt-tolerant and alkaliphilic actinomycete BS30 isolated from a Saharan soil sample of Algeria, exhibited...     

Inhibition of pathologic retinal neovascularization by alpha-defensins

Proliferative retinopathies, such as those complicating prematurity and diabetes, are major causes of blindness. A prominent feature of these retinopathies is excessive neovascularization, which is orchestrated by the hypoxia-induced vascular endothelial growth factor (VEGF) stimulating endothelial cells and the integrin-mediated adhesive interactions of endothelial cells with extracellular matrix components such as fibronectin (FN). Recently, we demonstrated that alpha-defensins interfere with alpha5beta1-FN interactions and dependent endothelial cell functions. Here, alpha-defensins were studied in hypoxia-induced proliferative retinopathy. In vitro, alpha-defensins specifically inhibited alpha5beta1-integrin-dependent migration of bovine retinal endothelial cells (BRECs) to FN, attenuated the VEGF-stimulated increase in endothelial permeability, and blocked BREC proliferation and capillary sprout formation in 3-dimensional fibrin-matrices. An up-regulation of beta1-integrin and FN was observed in the retinal vessels in the mouse model of hypoxia-induced retinal angiogenesis. Systemic and local administration of alpha-defensins reduced retinal neovascularization by 45% and 60%, respectively, and this effect was comparable to the inhibitory effect of alpha5beta1-blocking antibody. alpha-Defensins were detected in human diabetic retinas associated with normal retinal vessels but were absent from proliferative lesions. Together, these data show that alpha-defensins inhibit pathologic retinal neovascularization in vivo and may provide a clinically efficient strategy against proliferative retinopathies.