The biochemistry of drug metabolism-an introduction: part 7. Intra-individual factors affecting drug metabolism.

This review on intra-individual factors affecting drug metabolism completes our series on the biochemistry of drug metabolism. The article presents the molecular mechanisms causing intra-individual differences in enzyme expression and activity. They include enzyme induction by transcriptional activation and enzyme inhibition on the protein level. The influencing factors are of physiological, pathological, or external origin. Tissue characteristics and developmental age strongly influence enzyme-expression patterns. Further influencing factors are pregnancy, disease, or biological rhythms. Xenobiotics, drugs, constituents of herbal remedies, food constituents, ethanol, and tobacco can all influence enzyme expression or activity and, hence, affect drug metabolism.

Administration intra-vitréenne de liposomes pour la vectorisation de principes actifs [The use of liposomes as intravitreal drug delivery system].

Liposomes are vesicular lipidic systems allowing encapsulation of drugs. This article reviews the relevant issues in liposome structure (composition and size), and their influence on intravitreal pharmacokinetics. Liposome-mediated drug delivery to the posterior segment of the eye via intravitreal administration has been addressed by several authors and remains experimental. Liposomes have been used for intravitreal delivery of antibiotics, antivirals, antifungal drugs, antimetabolites, and cyclosporin. Encapsulation of these drugs within liposomes markedly increased their intravitreal half-life, and reduced their retinal toxicity. Liposomes have also shown an attractive potential for retinal gene transfer by intravitreal delivery of plasmids or oligonucleotides.

Adjuvant intra-arterial hepatic fotemustine for high-risk uveal melanoma patients.

Uveal melanoma metastases occur most commonly in the liver. Given the 50% mortality rate in patients at high risk of developing liver metastases, we tested an adjuvant intra-arterial hepatic (i.a.h.) chemotherapy with fotemustine after proton beam irradiation of the primary tumour. We treated 22 high-risk patients with adjuvant i.a.h. fotemustine. Planned treatment duration was 6 months, starting with four weekly doses of 100 mg/m(2), and after a 5-week rest, repeated every 3 weeks. The survival of this patient group was compared with that of a 3 : 1 matched control group randomly selected from our institutional database. Half of the patients experienced > or =grade 3 hepatotoxicity (one patient developing cholangitis 8 years later). Catheter-related complications occurred in 18%. With a median follow-up of 4.6 years for the fotemustine group and 8.5 years for the control group, median overall survival was 9 years [95% confidence interval (CI) 2.2-12.7] and 7.4 years (95% CI 5.4-12.7; P=0.5), respectively, with 5-year survival rates of 75 and 56%. Treatment with adjuvant i.a.h. fotemustine is feasible. However, toxicities are important. Although our data suggest a survival benefit, it was not statistically significant. Confirming such a benefit would require a large, internationally coordinated, prospective randomized trial.

Usefulness of intra-articular bupivacain and lidocain adjunction in MR or CT arthrography: a prospective study in 148 patients.

PURPOSE: To evaluate the influence of shorter- and longer-acting intra-articular anaesthetics on post-arthrographic pain. MATERIALS AND METHODS: 154 consecutive patients investigated by MR or CT arthrographies were randomly assigned to one of the following groups: 1--intra-articular contrast injection only; 2--lidocain 1% adjunction; or 3--bupivacain 0.25% adjunction. Pain was assessed before injection, at 15 min, 4 h, 1 day and 1 week after injection by visual analogue scale (VAS). RESULTS: At 15 min, early mean pain score increased by 0.96, 0.24 and 0 in groups 1, 2 and 3, respectively. Differences between groups 1 & 3 and 1 & 2 were statistically significant (p=0.003 and 0.03, respectively), but not between groups 2 & 3 (p=0.54). Delayed mean pain score increase was maximal at 4 h, reaching 1.60, 1.22 and 0.29 in groups 1, 2 and 3, respectively. Differences between groups 1 & 2 and 2 & 3 were statistically significant (p=0.002 and 0.02, respectively), but not between groups 1 & 2 (p=0.46). At 24 h and 1 week, the interaction of local anaesthetics with increase in pain score was no longer significant. Results were independent of age, gender and baseline VAS. CONCLUSION: Intra-articular anaesthesia may significantly reduce post-arthrographic pain. Bupivacain seems to be more effective than lidocain to reduce both early and delayed pain.

Cognitive issues in fingerprint analysis: Inter- and intra-expert consistency and the effect of a "target" comparison

Deciding whether two fingerprint marks originate from the same source requires examination and comparison of their features. Many cognitive factors play a major role in such information processing. In this paper we examined the consistency (both between- and within-experts) in the analysis of latent marks, and whether the presence of a 'target' comparison print affects this analysis. Our findings showed that the context of a comparison print affected analysis of the latent mark, possibly influencing allocation of attention, visual search, and threshold for determining a 'signal'. We also found that even without the context of the comparison print there was still a lack of consistency in analysing latent marks. Not only was this reflected by inconsistency between different experts, but the same experts at different times were inconsistent with their own analysis. However, the characterization of these inconsistencies depends on the standard and definition of what constitutes inconsistent. Furthermore, these effects were not uniform; the lack of consistency varied across fingerprints and experts. We propose solutions to mediate variability in the analysis of friction ridge skin.

Growth arrest-specific gene 6 (GAS6) as an intra-hospital mortality predictor for patients in septic shock

Aim: Gas6 is known to be elevated in sepsis, correlating with the severity of infection and organ failure. We aimed to investigate the performance of Gas6 plasma levels at admission to predict the risk of mortality in a cohort of septic patients.Methods: We used prospectively collected data and plasma samples from the 'Sepsis Cohorte Romande'. Gas6 level was measured by ELISA at admission and expressed in percentage relative to its level in a pool of normal plasma.Results: Non-survivors (n = 19) presented higher Gas6 levels than survivors (n = 78; median 287% vs. 158%, IQR 182 and 119 respectively; P = 0.0003). Gas6 correlated positively with different cytokine and was the best mortality predictor, as shown by the ROC curves area (Fig. 1). In patients with septic shock (n = 67), using 249% as a cut-off value, Gas6 measurement had a specificity of 81% and a sensitivity of 68% for predicting mortality. ROC curve area was 0.76. Positive and negative predictive values were 59% and 87%, respectively.Conclusion: Thus, Gas6 plasma level at admission might be a useful tool to predict mortality in patients with septic shock. Nevertheless, independent association of Gas6 level with mortality still needs to be assessed. Although Gas6 hold promise as an early sepsis marker, its precise implication in sepsis remains to be elucidated.

Melastatin Expression in Ocular Melanocytic Proliferations

Purpose: Melastatin (MLSN-1) belongs to the transient receptor potential (TRP) superfamilly of calcium-permeable channels, and has been reported to be a melanocyte-specific gene. In human cutaneous melanoma, MLSN-1 mRNA expression displays a pattern of inverse correlation to disease free survival. We describe the patterns of MLSN-1 mRNA expression in conjunctival nevi, conjunctival melanoma, and uveal melanoma. Methods: In situ hybridization using two S35-labelled riboprobes for MLSN-1 was performed on formalin-fixed, paraffin-embedded tissues. A control probe for H4 histone was used to confirm mRNA integrity in these archival tissues. The 21 ocular melanocytic lesions studied included 5 conjunctival nevi, 6 conjunctival melanomas, and 10 enucleated eyes with uveal melanoma. The minimal requirement for interpretation of MLSN-1 mRNA loss was the presence of only background signal in a focus of at least 5 adjacent melanocytic cells. Results: Ubiquitous expression of MLSN-1 mRNA was found in conjunctival melanocytes in the non-lesional epithelium adjacent to the conjunctival melanocytic proliferations and in all 5 conjunctival nevi studied. Four different patterns of MLSN-1 mRNA expression were observed in conjunctival melanomas: one case showed complete preservation of MLSN-1 mRNA, two cases showed diffuse scattered loss of MLSN-1 mRNA, two cases showed focal clonal loss of MLSN-1 mRNA expression, and one case had no detected MLSN-1 mRNA. In uveal melanomas, MLSN-1 mRNA expression was partially preserved in two cases, lost by a clearly delimited subset of tumor cells (focal clonal loss) in four cases, and was not detectable in the entire tumor in four cases. MLSN-1 mRNA expression was also found in the normal iris, ciliary and choroidal melanocytes as well as in the retinal pigmented epithelium and in the inner nuclear layer of the retina. Conclusions: The patterns of MLSN-1 mRNA expression in the ocular melanocytic proliferations are similar to those reported in cutaneous melanocytic proliferations. In the conjunctiva, MLSN-1 mRNA expression appeared to correlate with tumor progression; all the benign conjunctival nevi had preserved expression of MLSN-1 mRNA and most of the conjunctival melanomas partial or complete loss of expression. In uveal melanoma, patterns of melastatin expression ranging from partial preservation to complete loss were found. Additional studies of a large number of ocular melanocytic proliferations may show a correlation with tumor progression and prognosis similar to that observed in cutaneous melanoma.

Ocular and systemic bio-distribution of rhodamine-conjugated liposomes loaded with VIP injected into the vitreous of Lewis rats.

PURPOSE: Local delivery of therapeutic molecules encapsulated within liposomes is a promising method to treat ocular inflammation. The purpose of the present study was to define the biodistribution of rhodamine-conjugated liposomes loaded with vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, following their intravitreal (IVT) injection in normal rats. METHODS: Healthy seven- to eight-week-old Lewis male rats were injected into the vitreous with empty rhodamine-conjugated liposomes (Rh-Lip) or with VIP-loaded Rh-Lip (VIP-Rh-Lip; 50 mM of lipids with an encapsulation efficiency of 3.0+/-0.4 mmol VIP/mol lipids). Twenty-four h after IVT injection, the eyes, the cervical, mesenteric, and inguinal lymph nodes (LN), and spleen were collected. The phenotype and distribution of cells internalizing Rh-Lip and VIP-Rh-Lip were studied. Determination of VIP expression in ocular tissues and lymphoid organs and interactions with T cells in cervical LN was performed on whole mounted tissues and frozen tissue sections by immunofluorescence and confocal microscopy. RESULTS: In the eye, 24 h following IVT injection, fluorescent liposomes (Rh-Lip and VIP-Rh-Lip) were detected mainly in the posterior segment of the eye (vitreous, inner layer of the retina) and to a lesser extent at the level of the iris root and ciliary body. Liposomes were internalized by activated retinal Müller glial cells, ocular tissue resident macrophages, and rare infiltrating activated macrophages. In addition, fluorescent liposomes were found in the episclera and conjunctiva where free VIP expression was also detected. In lymphoid organs, Rh-Lip and VIP-Rh-Lip were distributed almost exclusively in the cervical lymph nodes (LN) with only a few Rh-Lip-positive cells detected in the spleen and mesenteric LN and none in the inguinal LN. In the cervical LN, Rh-Lip were internalized by resident ED3-positive macrophages adjacent to CD4 and CD8-positive T lymphocytes. Some of these T lymphocytes in close contact with macrophages containing VIP-Rh-Lip expressed VIP. CONCLUSIONS: Liposomes are specifically internalized by retinal Müller glial cells and resident macrophages in the eye. A limited passage of fluorescent liposomes from the vitreous to the spleen via the conventional outflow pathway and the venous circulation was detected. The majority of fluorescent liposomes deposited in the conjunctiva following IVT injection reached the subcapsular sinus of the cervical LN via conjuntival lymphatics. In the cervical LN, Rh-Lip were internalized by resident subcapsular sinus macrophages adjacent to T lymphocytes. Detection of VIP in both macrophages and T cells in cervical LN suggests that IVT injection of VIP-Rh-Lip may increase ocular immune privilege by modulating the loco-regional immune environment. In conclusion, our observations suggest that IVT injection of VIP-loaded liposomes is a promising therapeutic strategy to dampen ocular inflammation by modulating macrophage and T cell activation mainly in the loco-regional immune system.