Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test.

Two published case reports showed that addition of risperidone (1 and 2 mg/d) to a clozapine treatment resulted in a strong increase of clozapine plasma levels. As clozapine is metabolized by cytochrome P450 isozymes, a study was initiated to assess the in vivo interaction potential of risperidone on various cytochrome P450 isozymes. Eight patients were phenotyped with dextromethorphan (CYP2D6), mephenytoin (CYP2C19), and caffeine (CYP1A2) before and after the introduction of risperidone. Before risperidone, all eight patients were phenotyped as being extensive metabolizers of CYP2D6 and CYP2C19. Risperidone at dosages between 2 and 6 mg/d does not appear to significantly inhibit CYP1A2 and CYP2C19 in vivo (median plasma paraxanthine/caffeine ratios before and after risperidone: 0.65, 0.69; p = 0.89; median urinary (S)/(R) mephenytoin ratios before and after risperidone:0.11, 0.12; p = 0.75). Although dextromethorphan metabolic ratio is significantly increased by risperidone (median urinary dextromethorphan/dextrorphan ratios before and after risperidone: 0.010, 0.018; p = 0.042), risperidone can be considered a weak in vivo CYP2D6 inhibitor, as this increase is modest and none of the eight patients was changed from an extensive to a poor metabolizer. The reported increase of clozapine concentrations by risperidone can therefore not be explained by an inhibition of CYP1A2, CYP2D6, CYP2C19 or by any combination of the three.

Development of a multistrain bacterial bioreporter platform for the monitoring of hydrocarbon contaminants in marine environments.

Petroleum hydrocarbons are common contaminants in marine and freshwater aquatic habitats, often occurring as a result of oil spillage. Rapid and reliable on-site tools for measuring the bioavailable hydrocarbon fractions, i.e., those that are most likely to cause toxic effects or are available for biodegradation, would assist in assessing potential ecological damage and following the progress of cleanup operations. Here we examined the suitability of a set of different rapid bioassays (2-3 h) using bacteria expressing the LuxAB luciferase to measure the presence of short-chain linear alkanes, monoaromatic and polyaromatic compounds, biphenyls, and DNA-damaging agents in seawater after a laboratory-scale oil spill. Five independent spills of 20 mL of NSO-1 crude oil with 2 L of seawater (North Sea or Mediterranean Sea) were carried out in 5 L glass flasks for periods of up to 10 days. Bioassays readily detected ephemeral concentrations of short-chain alkanes and BTEX (i.e., benzene, toluene, ethylbenzene, and xylenes) in the seawater within minutes to hours after the spill, increasing to a maximum of up to 80 muM within 6-24 h, after which they decreased to low or undetectable levels. The strong decrease in short-chain alkanes and BTEX may have been due to their volatilization or biodegradation, which was supported by changes in the microbial community composition. Two- and three-ring PAHs appeared in the seawater phase after 24 h with a concentration up to 1 muM naphthalene equivalents and remained above 0.5 muM for the duration of the experiment. DNA-damage-sensitive bioreporters did not produce any signal with the oil-spilled aqueous-phase samples, whereas bioassays for (hydroxy)biphenyls showed occasional responses. Chemical analysis for alkanes and PAHs in contaminated seawater samples supported the bioassay data, but did not show the typical ephemeral peaks observed with the bioassays. We conclude that bacterium-based bioassays can be a suitable alternative for rapid on-site quantitative measurement of hydrocarbons in seawater.

Frequency-dependent attenuation as a potential indicator of oil saturation

At seismic frequencies, wave-induced fluid flow is a major cause of P-wave attenuation in partially saturated porous rocks. Attenuation is of great importance for the oil industry in the interpretation of seismic field data. Here, the effects on P-wave attenuation resulting from changes in oil saturation are studied for media with coexisting water, oil, and gas. For that, creep experiments are numerically simulated by solving Biot's equations for consolidation of poroelastic media with the finite-element method. The experiments yield time-dependent stress?strain relations that are used to calculate the complex P-wave modulus from which frequency-dependent P-wave attenuation is determined. The models are layered media with periodically alternating triplets of layers. Models consisting of triplets of layers having randomly varying layer thicknesses are also considered. The layers in each triplet are fully saturated with water, oil, and gas. The layer saturated with water has lower porosity and permeability than the layers saturated with oil and gas. These models represent hydrocarbon reservoirs in which water is the wetting fluid preferentially saturating regions of lower porosity. The results from the numerical experiments showed that increasing oil saturation, connected to a decrease in gas saturation, resulted in a significant increase of attenuation at low frequencies (lower than 2 Hz). Furthermore, replacing the oil with water resulted in a distinguishable behavior of the frequency-dependent attenuation. These results imply that, according to the physical mechanism of wave-induced fluid flow, frequency-dependent attenuation in media saturated with water, oil, and gas is a potential indicator of oil saturation.

Generalist hydrocarbon-degrading bacterial communities in the oil-polluted water column of the North Sea.

The aim of this work was to determine the effect of light crude oil on bacterial communities during an experimental oil spill in the North Sea and in mesocosms (simulating a heavy, enclosed oil spill), and to isolate and characterize hydrocarbon-degrading bacteria from the water column. No oil-induced changes in bacterial community (3 m below the sea surface) were observed 32 h after the experimental spill at sea. In contrast, there was a decrease in the dominant SAR11 phylotype and an increase in Pseudoalteromonas spp. in the oiled mesocosms (investigated by 16S rRNA gene analysis using denaturing gradient gel electrophoresis), as a consequence of the longer incubation, closer proximity of the samples to oil, and the lack of replenishment with seawater. A total of 216 strains were isolated from hydrocarbon enrichment cultures, predominantly belonging to the genus Pseudoaltero monas; most strains grew on PAHs, branched and straight-chain alkanes, as well as many other carbon sources. No obligate hydrocarbonoclastic bacteria were isolated or detected, highlighting the potential importance of cosmopolitan marine generalists like Pseudoalteromonas spp. in degrading hydrocarbons in the water column beneath an oil slick, and revealing the susceptibility to oil pollution of SAR11, the most abundant bacterial clade in the surface ocean.

Oxidative potential of particles in different occupational environments: a pilot study

The oxidative potential (OP) of particulate matter has been proposed as a toxicologically relevant metric. This concept is already frequently used for hazard characterization of ambient particles but it is still seldom applied in the occupational field. The objective of this study was to assess the OP in two different types of workplaces and to investigate the relationship between the OP and the physicochemical characteristics of the collected particles. At a toll station, at the entrance of a tunnel ('Tunnel' site), and at three different mechanical yards ('Depot' sites), we assessed particle mass (PM4 and PM2.5 and size distribution), number and surface area, organic and elemental carbon, polycyclic aromatic hydrocarbon (PAH), and four quinones as well as iron and copper concentration. The OP was determined directly on filters without extraction by using the dithiothreitol assay (DTT assay-OP(DTT)). The averaged mass concentration of respirable particles (PM4) at the Tunnel site was about twice the one at the Depot sites (173±103 and 90±36 µg m(-3), respectively), whereas the OP(DTT) was practically identical for all the sites (10.6±7.2 pmol DTT min(-1) μg(-1) at the Tunnel site; 10.4±4.6 pmol DTT min(-1) μg(-1) at the Depot sites). The OP(DTT) of PM4 was mostly present on the smallest PM2.5 fraction (OP(DTT) PM2.5: 10.2±8.1 pmol DTT min(-1) μg(-1); OP(DTT) PM4: 10.5±5.8 pmol DTT min(-1) μg(-1) for all sites), suggesting the presence of redox inactive components in the PM2.5-4 fraction. Although the reactivity was similar at the Tunnel and Depot sites irrespective of the metric chosen (OP(DTT) µg(-1) or OP(DTT) m(-3)), the chemicals associated with OP(DTT) were different between the two types of workplaces. The organic carbon, quinones, and/or metal content (Fe, Cu) were strongly associated with the DTT reactivity at the Tunnel site whereas only Fe and PAH were associated (positively and negatively, respectively) with this reactivity at the Depot sites. These results demonstrate the feasibility of measuring of the OP(DTT) in occupational environments and suggest that the particulate OP(DTT) is integrative of different physicochemical properties. This parameter could be a potentially useful exposure proxy for investigating particle exposure-related oxidative stress and its consequences. Further research is needed mostly to demonstrate the association of OP(DTT) with relevant oxidative endpoints in humans exposed to particles.

Biological materials in colorectal surgery: current applications and potential for the future.

Biological materials are increasingly used in abdominal surgery for ventral, pelvic and perineal reconstructions, especially in contaminated fields. Future applications are multi-fold and include prevention and one-step closure of infected areas. This includes prevention of abdominal, parastomal and pelvic hernia, but could also include prevention of separation of multiple anastomoses, suture- or staple-lines. Further indications could be a containment of infected and/or inflammatory areas and protection of vital implants such as vascular grafts. Reinforcement patches of high-risk anastomoses or unresectable perforation sites are possibilities at least. Current applications are based mostly on case series and better data is urgently needed. Clinical benefits need to be assessed in prospective studies to provide reliable proof of efficacy with a sufficient follow-up. Only superior results compared with standard treatment will justify the higher costs of these materials. To date, the use of biological materials is not standard and applications should be limited to case-by-case decision.

Acute flare induced by the calcific tendonitis of the rotator cuff: inhibition of IL-1 a potential therapeutic target?

Introduction: Calcific tendonitis of rotator cuff is observed on plainradiographs in 10% of adults, but remains asymptomatic in half thesecases. Sometimes, these calcifications induce acute flares withmassive inflammation similar to gout or CPPD crisis. Analgesics/anti-inflammatory medications are usually not sufficient to controlssymptoms in these situations. Local steroid infiltration with or withoutremoval of the calcific deposition with a needle aspiration may beuseful. A new approach could be IL-1 inhibitors. Indeed, basic calciumphosphate crystals are capable of stimulating the release of activeIL-1β in vitro. These crystals trigger IL-1β release, in an analogousmanner to MSU crystals in acute gout, suggesting that IL-1β blockademay be clinically useful.Case presentation: This report describes a 70-year old woman withacute rest pain of the right shoulder since 48 hours. On examination,we found massive limitations of active and passive movements. Thepatient evaluated, on the visual scale, her symptoms at 10/10 the nightand 5/10 the day. The radiography and showed a rounded, 8 mmcalcification in the subscapularis tendon. The ultrasound aspectrevealed a heterogeneous calcification partially non solid, surroundedby massive inflammation on Doppler. C-reactive protein anderythrocyte sedimentation rate were high (74 mg/ml, 54 mm/hour).The patient received subcutaneous injections of anakinra: 100 mgdaily for 3 days (D1-D3). We evaluated the patient in our consult at dayD1, D2, D3, D7, D16 and by phone at D70.This treatment rapidly relieved the inflammatory symptoms (within afew hours with no relapse). The mobility of the shoulder, the biologicsparameters improved and the size of the calcification as well thedegree of inflammation regressed on ultrasound after 3 days.Conclusion: This is the first report of a woman with an acute flareinduced by calcific tendonitis who received anakinra. IL-1 inhibitionmay be a therapeutic target in calcific tendonitis. To analyse thisresponse more precisely and elaborate definitive conclusions, aprospective pilot study is on-going in our ambulatory institute.

Microbiota abnormalities in inflammatory airway diseases - Potential for therapy.

Increasingly the development of novel therapeutic strategies is taking into consideration the contribution of the intestinal microbiota to health and disease. Dysbiosis of the microbial communities colonizing the human intestinal tract has been described for a variety of chronic diseases, such as inflammatory bowel disease, obesity and asthma. In particular, reduction of several so-called probiotic species including Lactobacilli and Bifidobacteria that are generally considered to be beneficial, as well as an outgrowth of potentially pathogenic bacteria is often reported. Thus a tempting therapeutic approach is to shape the constituents of the microbiota in an attempt to restore the microbial balance towards the growth of 'health-promoting' bacterial species. A twist to this scenario is the recent discovery that the respiratory tract also harbors a microbiota under steady-state conditions. Investigators have shown that the microbial composition of the airway flora is different between healthy lungs and those with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease as well as cystic fibrosis. This is an emerging field, and thus far there is very limited data showing a direct contribution of the airway microbiota to the onset and progression of disease. However, should future studies provide such evidence, the airway microbiota might soon join the intestinal microbiota as a target for therapeutic intervention. In this review, we highlight the major advances that have been made describing the microbiota in chronic lung disease and discuss current and future approaches concerning manipulation of the microbiota for the treatment and prevention of disease.

Membrane potential dynamics of neocortical projection neurons driving target-specific signals.

Primary sensory cortex discriminates incoming sensory information and generates multiple processing streams toward other cortical areas. However, the underlying cellular mechanisms remain unknown. Here, by making whole-cell recordings in primary somatosensory barrel cortex (S1) of behaving mice, we show that S1 neurons projecting to primary motor cortex (M1) and those projecting to secondary somatosensory cortex (S2) have distinct intrinsic membrane properties and exhibit markedly different membrane potential dynamics during behavior. Passive tactile stimulation evoked faster and larger postsynaptic potentials (PSPs) in M1-projecting neurons, rapidly driving phasic action potential firing, well-suited for stimulus detection. Repetitive active touch evoked strongly depressing PSPs and only transient firing in M1-projecting neurons. In contrast, PSP summation allowed S2-projecting neurons to robustly signal sensory information accumulated during repetitive touch, useful for encoding object features. Thus, target-specific transformation of sensory-evoked synaptic potentials by S1 projection neurons generates functionally distinct output signals for sensorimotor coordination and sensory perception.

Potentiel des liposomes pour l'injection intravitréenne de molécules thérapeutiques [Potential of liposomes for the intravitreal injection of therapeutic molecules].

Intravitreal administration has been widely used since 20 years and has been shown to improve the treatment of diseases of the posterior segment of the eye with infectious origin or in edematous maculopathies. This route of administration allows to achieve high concentration of drug in the vitreous and avoids the problems resulting from systemic administration. However, two basic problems limit the use of intravitreal therapy. Many drugs are rapidly cleared from the vitreous humor; therefore, to reach and to maintain effective therapy repeated injections are necessary. Repeated intravitreal injections increase the risk of endophthalmitis, damage to lens, retinal detachment. Moreover, some drugs provoke a local toxicity at their effective dose inducing side-effects and possible retinal lesions. In this context, the development and the use of new drug delivery systems for intravitreal administration are necessary to treat chronic ocular diseases. Among them, particulate systems such as liposomes have been widely studied. Liposomes are easily injectable and permit to reduce the toxicity and to increase the residence time of several drugs in the eye. They are also able to protect in vivo poorly-stable molecules from degradation such as peptides and nucleic acids. Some promising results have been obtained for the treatment of retinitis induced by cytomegalovirus in human and more recently for the treatment of uveitis in animal. Finally, the fate of liposomes in ocular tissues and fluids after their injection into the vitreous and their elimination routes begin to be more known.

Alveolar echinococcosis of the liver: Diffusion-weighted MRI findings and potential role in lesion characterisation

PURPOSE: To report the diffusion-weighted MRI findings in alveolar echinococcosis (AE) of the liver and evaluate the potential role of apparent diffusion coefficients (ADCs) in the characterisation of lesions. MATERIALS AND METHODS: We retrospectively included 22 patients with 63 AE liver lesions (≥1cm), examined with 3-T liver MRI, including a free-breathing diffusion-weighted single-shot echo-planar imaging sequence (b-values=50, 300 and 600s/mm(2)). Two radiologists jointly assessed the following lesion features: size, location, presence of cystic and/or solid components (according to Kodama's classification system), relative contrast enhancement, and calcifications (on CT). The ADCtotal, ADCmin and ADCmax were measured in each lesion and the surrounding liver parenchyma. RESULTS: Three type 1, 19 type 2, 17 type 3, three type 4 and 21 type 5 lesions were identified. The mean (±SD) ADCtotal, ADCmin and ADCmax for all lesions were 1.73±0.50, 0.76±0.38 and 2.63±0.76×10(-3)mm(2)/s, respectively. The mean ADCtotal for type 1, type 2, type 3, type 4 and type 5 lesions were 1.97±1.01, 1.76±0.53, 1.73±0.41, 1.15±0.42 and 1.76±0.44×10(-3)mm(2)/s, respectively. No significant differences were found between the five lesion types, except for type 4 (p=0.0363). There was a significant correlation between the presence of a solid component and low ADCmin (r=0.39, p=0.0016), whereas an inverse correlation was found between the relative contrast enhancement and ADCtotal (r=-0.34, p=0.0072). CONCLUSION: The ADCs of AE lesions are relatively low compared to other cystic liver lesions, which may help in the differential diagnosis. Although ADCs are of little use to distinguish between the five lesion types, their low value reflects the underlying solid component.

Oxidative potential for fine/ultrafine particles in occupational situations

Introduction : The redox properties of fine/ultrafine particles as well as nanoparticles (NP) are suggested to be important to explain their biological activity and could constitute a novel and promising metric for hazard evaluation. The acellular in vitro dithiothreitol (DTT) assay allows measuring this property. Objectives : (1) to evaluate sampling requirements for fine/ultrafine particle allowing measurement of their oxidative potential (2) to apply the methodology to occupational situations where particle from combustion sources are generated. Material and method : Sampling parameters (type of filters and loaded amount) and storage duration affecting the DTT measurements were evaluated. Based on these results, a methodological approach was defined and applied in two occupational situations where diesel and other combustion particles are present (toll station in a tunnel and mechanical yard for bus reparation). Results : Teflon filters loaded with diesel particles were found more suitable for the DTT assay, due to their better chemical inertness compared to quartz filters: after storage durations larger than 150 hours, an increased reactivity toward DTT was observed only with quartz filters. Reactivity was linearly correlated to the loaded mass until about 1000 μg/filter. Different redox reactivities were determined in both working places, with the mechanical yard presenting a higher DTT consumption rate. Discussion and conclusions : These results demonstrate the feasibility of this method to determine the oxidative potential of fine/ultrafine particles in occupational situations. We propose to include this approach for hazard assessment of work places with exposure to manufactured and other NP.

Oligomerization of the alpha 1a- and alpha 1b-adrenergic receptor subtypes. Potential implications in receptor internalization.

We combined biophysical, biochemical, and pharmacological approaches to investigate the ability of the alpha 1a- and alpha 1b-adrenergic receptor (AR) subtypes to form homo- and hetero-oligomers. Receptors tagged with different epitopes (hemagglutinin and Myc) or fluorescent proteins (cyan and green fluorescent proteins) were transiently expressed in HEK-293 cells either individually or in different combinations. Fluorescence resonance energy transfer measurements provided evidence that both the alpha 1a- and alpha 1b-AR can form homo-oligomers with similar transfer efficiency of approximately 0.10. Hetero-oligomers could also be observed between the alpha 1b- and the alpha 1a-AR subtypes but not between the alpha 1b-AR and the beta2-AR, the NK1 tachykinin, or the CCR5 chemokine receptors. Oligomerization of the alpha 1b-AR did not require the integrity of its C-tail, of two glycophorin motifs, or of the N-linked glycosylation sites at its N terminus. In contrast, helix I and, to a lesser extent, helix VII were found to play a role in the alpha 1b-AR homo-oligomerization. Receptor oligomerization was not influenced by the agonist epinephrine or by the inverse agonist prazosin. A constitutively active (A293E) as well as a signaling-deficient (R143E) mutant displayed oligomerization features similar to those of the wild type alpha 1b-AR. Confocal imaging revealed that oligomerization of the alpha1-AR subtypes correlated with their ability to co-internalize upon exposure to the agonist. The alpha 1a-selective agonist oxymetazoline induced the co-internalization of the alpha 1a- and alpha 1b-AR, whereas the alpha 1b-AR could not co-internalize with the NK1 tachykinin or CCR5 chemokine receptors. Oligomerization might therefore represent an additional mechanism regulating the physiological responses mediated by the alpha 1a- and alpha 1b-AR subtypes.