Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers

Steady-state blood concentrations of (R)- methadone (i.e., the active form), (S)-methadone, and (R,S)-methadone were measured before and after introduction of paroxetine 20 mg/day during a mean period of 12 days in 10 addict patients in methadone maintenance treatment. Eight patients were genotyped as CYP2D6 homozygous extensive metabolizers (EMs) and two patients as poor metabolizers (PMs). Paroxetine significantly increased concentrations of both enantiomers of methadone in the whole group (mean increase for (R)-methadone +/- SD, 26 +/- 32%; range, -14% to +83%, p = 0.032; for (S)-methadone, 49 +/- 51%; range, -29% to +137%, p = 0.028; for (R,S)-methadone, 35 +/- 41%; range, -20% to +112%, p = 0.032) and in the group of eight EMs (mean increase, 32%, p = 0.036; 53%, p = 0.028; and 42%, p = 0.036, for (R)-methadone, (S)-methadone, and (R,S)-methadone, respectively). On the other hand, in the two PMs, (S)-methadone but not (R)-methadone concentrations were increased by paroxetine (mean increases of 36% and 3%, respectively). Paroxetine is a strong CYP2D6 inhibitor, and these results confirm previous studies showing an involvement of CYP2D6 in methadone metabolism with a stereoselectivity toward the (R)-enantiomer. Because paroxetine is a mild inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, increase of (S)-methadone concentrations in both EMs and PMs could be mediated by inhibition of any of these isozymes.     

Eumelanin is a Major Determinant for2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) Incorporation into Hair of Mice

Mice with different hair pigmentation were studied to evaluate the role of melanin in the incorporation of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) into hair. Mice C57BL/6J‐c2j/+ (white), C57BL/6J‐Ay (yellow), C57L/J (grey), C57BR/cdJ (brown) and C57BL/6J (black) were dosed with PhIP: 7–9 days old (total amount: 0.006 or 0.58 mg/kg b.wt., for 4 days) and adults (total amount 50 mg/kg b.wt. during 8 weeks). Hair was collected either 30 days after the last PhIP administration (new‐born mice) or 8 weeks after the first administration (adult mice). PhIP was incorporated into black hair to a greater extent than into brown, grey, yellow and non‐pigmented hair. The concentration of PhIP in the hair of new‐born mice exposed to 0.58 mg PhIP/kg b.wt. were (mean±S.D.): 328±135 (black), 134±41 (brown), 9.1±1.2 (yellow) and 5.2±1.4 (white) ng/g hair. The PhIP concentrations in the hair of adult mice exposed to 50 mg/kg b.wt. were: 4750±1449 (black), 810±235 (brown), 541±119 (grey), 35.5±4.6 (yellow) and 21.6±8.8 (white) ng/g, and the eumelanin hair concentration in the same animals decreased in a similar pattern. A linear relationship (r²=1.00, P<0.0001) between the relative PhIP incorporation and the eumelanin concentration in hair was found.     

Improvement of post-transplant lymphocele treatment in the laparoscopic era

Post-transplant lymphoceles are a common problem after renal transplantation, often inflicting the graft or adjacent iliac veins. Since 1991, there have been many reports on laparoscopic fenestration as the treatment of choice, but no larger series has been presented. At our department, 63 laparoscopic procedures were performed between 1993 and 2001 among 1502 renal graft recipients. The laparoscopic operation time, conversion rate, hospital stay, and complications have all decreased progessively. Duration of hospital stay and convalescence was markedly longer in patients treated with conventional open surgery (27 patients). Rejections, CMV disease, and post-transplant reoperations seem to have an increased incidence in the lymphocele population. According to our experience, laparoscopic fenestration is the superior treatment for symptomatic lymphoceles, allowing minimal trauma and fast recovery. Our series suggests that the rate of complications/graft injury decreases progressively with experience. Laparoscopic ultrasound seems useful in difficult cases. Prophylactic measures should be emphasised at the time of transplantation and reoperations.     

Glycosaminoglycans and their synthetic mimetics inhibit RANTES-induced migration and invasion of human hepatoma cells

The CC-chemokine regulated on activation, normal T-cell expressed, and presumably secreted (RANTES)/CCL5 mediates its biological activities through activation of G protein-coupled receptors, CCR1, CCR3, or CCR5, and binds to glycosaminoglycans. This study was undertaken to investigate whether this chemokine is involved in hepatoma cell migration or invasion and to modulate these effects in vitro by the use of glycosaminoglycan mimetics. We show that the human hepatoma Huh7 and Hep3B cells express RANTES/CCL5 G protein-coupled receptor CCR1 but not CCR3 nor CCR5. RANTES/CCL5 binding to these cells depends on CCR1 and glycosaminoglycans. Moreover, RANTES/CCL5 strongly stimulates the migration and the invasion of Huh7 cells and to a lesser extent that of Hep3B cells. RANTES/CCL5 also stimulates the tyrosine phosphorylation of focal adhesion kinase and activates matrix metalloproteinase-9 in Huh7 hepatoma cells, resulting in increased invasion of these cells. The fact that RANTES/CCL5-induced migration and invasion of Huh7 cells are both strongly inhibited by anti-CCR1 antibodies and heparin, as well as by beta-d-xyloside treatment of the cells, suggests that CCR1 and glycosaminoglycans are involved in these events. We then show by surface plasmon resonance that synthetic glycosaminoglycan mimetics, OTR4120 or OTR4131, directly bind to RANTES/CCL5. The preincubation of the chemokine with each of these mimetics strongly inhibited RANTES-induced migration and invasion of Huh7 cells. Therefore, targeting the RANTES-glycosaminoglycan interaction could be a new therapeutic approach for human hepatocellular carcinoma.     

Risk factors for metabolic syndrome after liver transplantation: A systematic review and meta-analysis

Introduction

Metabolic syndrome is associated with increased risk of cardiovascular events, which contributes to the elevated mortality rate among liver transplant recipients. The objective of this systematic review and meta-analysis was to assess the prevalence and risk factors for metabolic syndrome after liver transplantation.

In vivo MR tracking of therapeutic microglia to a human glioma model

A knowledge of the spatial localization of cell vehicles used in gene therapy against glioma is necessary before launching therapy. For this purpose, MRI cell tracking is performed by labeling the cell vehicles with contrast agents. In this context, the goal of this study was to follow noninvasively the chemoattraction of therapeutic microglial cells to a human glioma model before triggering therapy. Silica nanoparticles grafted with gadolinium were used to label microglia. These vehicles, expressing constitutively the thymidine kinase suicide gene fused to the green fluorescent protein gene, were injected intravenously into human glioma-bearing nude mice. MRI was performed at 4.7 T to track noninvasively microglial accumulation in the tumor. This was followed by microscopy on brain slices to assess the presence in the glioma of the contrast agents, microglia and fusion gene through the detection of silica nanoparticles grafted with tetramethyl rhodamine iso-thiocyanate, 3,3'-dioctadecyloxacarbocyanine perchlorate and green fluorescent protein fluorescence, respectively. Finally, gancyclovir was administered systemically to mice. Human microglia were detectable in living mice, with strong negative contrast on T(2) *-weighted MR images, at the periphery of the glioma only 24 h after systemic injection. The location of the dark dots was identical in MR microscopy images of the extracted brains at 9.4 T. Fluorescence microscopy confirmed the presence of the contrast agents, exogenous microglia and suicide gene in the intracranial tumor. In addition, gancyclovir treatment allowed an increase in mice survival time. This study validates the MR tracking of microglia to a glioma after systemic injection and their use in a therapeutic strategy against glioma.     

Cortical responses to the mirror box illusion: a high-resolution EEG study

The mirror box illusion has proven a helpful therapy in pathologies such as phantom limb pain, and although the effect has been suggested to be a result of the interaction between pain, vision, touch, and proprioception, the mechanisms are still unknown. Multichannel (124) brain responses were investigated in healthy men (N = 11) and women (N = 14) during the mirror box illusion. Tactile somatosensory evoked potentials were recorded from the right thumb during two control conditions and two illusions: (control 1) no mirror: looking at the physical right thumb during stimulation, (control 2) no mirror: looking at the physical left thumb during stimulation, (illusion 1) mirror: the illusion that both thumbs were stimulated, and (illusion 2) mirror: the illusion that none of the thumbs were stimulated. In men, a significant medial shift in the y coordinate of the N70 dipole in illusion 2 (P = 0.021) was found when compared with illusion 1. No dipole shift was found for women. Additionally, men showed higher prevalence of P180 cingulate cortex activation during illusion 2 when compared with control 1 and 2 (P = 0.002). During illusion 2, the degree of conformity with the statement "The hand in the mirror feels like my other hand" was negatively correlated with the N70 x coordinate for men and positively correlated with the N70 z coordinate for women. In conclusion, short-term cortical plasticity can be induced by a mismatch between visual input and location of tactile stimulation in men. The present study suggests that gender differences exist in the perception of the mirror box illusion.