Differential semantic processing in patients with schizophrenia versus bipolar disorder: an N400 study.

OBJECTIVE: Both bipolar disorder (BD) and schizophrenia (SZ) are associated with language and thought symptoms that probably reflect a semantic memory-related impairment. We conducted a preliminary study to explore the nature of semantic processing in these disorders, using event-related potentials (ERPs). METHODS: Twelve patients with BD, 10 patients with SZ and a matched group of 21 healthy controls (HC) underwent EEG recording while they heard sentences containing homophones or control words and performed a semantic ambiguity resolution task on congruent or incongruent targets. RESULTS: Mean N400 amplitude differed between groups for homophones. Patients with SZ made more resolution errors than HC and exhibited a greater N400 congruity effect in ambiguous conditions than BD. In BD, the opposite N400 congruity effect was observed in ambiguous conditions. CONCLUSION: Results indicated differences in semantic processing between BD and SZ. Further studies with larger populations are needed in order to develop neurophysiological markers of these disorders. SIGNIFICANT OUTCOMES: In ambiguous conditions, patients with SZ exhibited a greater N400 difference between congruent and incongruent conditions than patients with BD.In ambiguous conditions, patients with SZ exhibited greater N400 amplitude in incongruent conditions than in congruent ones, whereas patients with BD exhibited the opposite N400 congruity effect.Ambiguity resolution results suggest that patients with SZ have difficulty considering the context, while patients with BD overactivate the dominant meaning of homophones and have difficulty inhibiting it.

Impact of two different colistin dosing strategies on healthy piglet fecal microbiota.

Colistin is often used in piglets but underdosing and overdosing are frequent. The impact of such administrations on fecal microbiota was studied. Piglets were given either underdoses of colistin by oral gavage for five days or overdoses by in-feed medication for 14days. The composition of fecal microbiota was studied by quantitative PCR, 16S rRNA sequencing, culture of Enterobacteriaceae, and quantification of short-chain fatty acids (SCFAs). The mean colistin concentrations during the treatment for underdosed and overdosed groups were 14.4µg/g and 64.9µg/g of feces respectively. Whatever the piglet and the sampling day, the two main phyla were Firmicutes and Bacteroidetes, The main families were Lactobacillaceae, Clostridiales, Lachnospiraceae and Ruminococcaceae. The main perturbation was the significant but transitory decrease in the Escherichia coli population during treatment, yet all the E. coli isolates were susceptible to colistin. Moreover, colistin did not affect the production of SCFAs. These results show that under- or overdoses of colistin do not result in any major disturbance of piglet fecal microbiota and rarely select for chromosomal resistance in the dominant E. coli population.

Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis.

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [fAUC]/MIC of >10 and fAUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests an a priori clear and easy to follow dosing strategy for CMS in ICU-HD patients.

New colistin population pharmacokinetic data in critically ill patients suggesting an alternative loading dose rationale.

Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

A preclinical pharmacokinetic modeling approach to the biopharmaceutical characterization of immediate and microsphere-based sustained release pulmonary formulations of rifampicin.

A rifampicin-hydroxypropyl-beta-cyclodextrin (RIF-HPCD) complex solution and two RIF-loaded PLGA microspheres with slow or fast release rates were nebulized into the rat lungs for a comparative biopharmaceutical evaluation. A pharmacokinetic model was applied to model systemic RIF concentrations and to predict the RIF concentrations in the lung epithelial lining fluid (ELF). With intravenous RIF and nebulized RIF-HPCD, plasma profiles and predicted RIF ELF profiles were superimposed indicating that RIF diffused almost instantaneously through the broncho-alveolar barrier. 5h post administration RIF ELF predicted concentrations were in agreement with experimental concentrations determined using the broncho-alveolar lavage (BAL) sampling method. Microsphere formulations resulted in different plasma concentration profiles, demonstrating RIF sustained release. The PK model predicted the ELF concentrations to be much higher with microspheres than with nebulized and IV RIF, over a prolonged time period, which was confirmed by BAL sampling. In conclusion this work demonstrated the benefit of using sustained-release microspheres administered as aerosols to maintain, over a prolonged time period, high levels of pulmonary concentrations of drugs characterized by a rapid absorption through the broncho-alveolar barrier. Moreover, PK modeling was a useful tool to build concentration-versus-time profiles in non-readily accessible ELF compartment and to assess the biopharmaceutical properties of aerosol formulations for lung delivery.

Pharmacokinetics of colistin and colistimethate sodium after a single 80-mg intravenous dose of CMS in young healthy volunteers.

Colistin pharmacokinetics (PK) was investigated in young healthy volunteers after a 1-h infusion of 80 mg (1 million international units (MIU)) of the prodrug colistin methanesulfonate (CMS). Concentration levels of CMS and colistin were determined in plasma and urine using a new chromatographic assay and analyzed simultaneously with a population approach after correcting the urine-related data for postexcretion hydrolysis of CMS into colistin. CMS and colistin have low volumes of distribution (14.0 and 12.4 liters, respectively), consistent with distribution being restricted to extracellular fluid. CMS is mainly excreted unchanged in urine (70% on average), with a typical renal clearance estimated at 103 ml/min-close to the glomerular filtration rate. Colistin elimination is essentially extrarenal, given that its renal clearance is 1.9 ml/min, consistent with extensive reabsorption. Colistin elimination is not limited by the formation rate because its half-life (3 h) is longer than that of CMS. The values of these pharmacokinetic parameters will serve as reference points for future comparisons with patients' data.

Clinical, microbiological, and immunological effects of fructo-oligosaccharide in patients with Crohn's disease.

BACKGROUND AND AIMS: The intestinal microbiota play a pivotal role in the inflammation associated with Crohn's disease through their interaction with the mucosal immune system. Some bifidobacteria species are immunoregulatory and induce increased dendritic cell interleukin 10 (IL-10) release in vitro. Fructo-oligosaccharides (FOS) increase faecal and mucosal bifidobacteria in healthy volunteers. The aim of this study was to assess the effect of FOS administration on disease activity, bifidobacteria concentrations, and mucosal dendritic cell function in patients with moderately active Crohn's disease. PATIENTS AND METHODS: Ten patients with active ileocolonic Crohn's disease received 15 g of FOS for three weeks. Disease activity was measured using the Harvey Bradshaw index. Faecal and mucosal bifidobacteria were quantified by fluorescence in situ hybridisation, and mucosal dendritic cell IL-10 and Toll-like receptor (TLR) expression were assessed by flow cytometry of dissociated rectal biopsies. RESULTS: FOS induced a significant reduction in the Harvey Bradshaw index from 9.8 (SD 3.1) to 6.9 (3.4) (p<0.01). There was a significant increase in faecal bifidobacteria concentration from 8.8 (0.9) log(10) to 9.4 (0.9) log(10) cells/g dry faeces (p<0.001). The percentage of IL-10 positive dendritic cells increased from 30 (12)% to 53 (10)% (p=0.06). Finally, the percentage of dendritic cells expressing TLR2 and TLR4 increased from 1.7 (1.7)% to 36.8 (15.9)% (p=0.08) and from 3.6 (3.6)% to 75.4 (3.4)% (p<0.001), respectively. CONCLUSIONS: FOS supplementation increases faecal bifidobacteria concentrations and modifies mucosal dendritic cell function. This novel therapeutic strategy appears to decrease Crohn's disease activity in a small open label trial and therefore warrants further investigation.

Intrusion and extrusion of water in hydrophobic mesopores.

We present experimental and theoretical results on intrusion-extrusion cycles of water in hydrophobic mesoporous materials, characterized by independent cylindrical pores. The intrusion, which takes place above the bulk saturation pressure, can be well described using a macroscopic capillary model. Once the material is saturated with water, extrusion takes place upon reduction of the externally applied pressure. Our results for the extrusion pressure can only be understood by assuming that the limiting extrusion mechanism is the nucleation of a vapor bubble inside the pores. A comparison of calculated and experimental nucleation pressures shows that a proper inclusion of line tension effects is necessary to account for the observed values of nucleation barriers. Negative line tensions of order 10(-11) J m(-1) are found for our system, in reasonable agreement with other experimental estimates of this quantity.

Dissipative water intrusion in hydrophobic MCM-41 type materials.

Texture-related features of water intrusion in hydrophobised MCM-41 silicas render these materials especially suitable for energy dissipation in mechanical dampers.

Bioavailability of melatonin in humans after day-time administration of D(7) melatonin.

Absolute bioavailability of the neurohormone melatonin (MLT) was studied in 12 young healthy volunteers (six males, six females) after administration at midday, on two separate occasions, of 23 microg by intravenous (i.v.) infusion and 250 microg by oral solution of D(7) MLT, a molecule in which seven deuterium atoms replace seven hydrogen atoms. Exogenous (D(7)) and endogenous (D(0)) MLT were quantified simultaneously but separately by a highly specific assay: gas chromatography/negative ion chemical ionization mass spectrometry, developed in our laboratory, which enabled us to go down to 0.5 pg/mL in plasma samples. After i.v. administration, the maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve (AUC) values were significantly different in male and female subjects, but there was no significant gender difference in total body clearance normalized to body weight: 1.27+/-0.20 L/h/kg and 1.18+/-0.22 L/h/kg for males and females, respectively. The apparent terminal half-life (t(1/2(z))) values were 36+/-2 and 41+/-10 min, respectively. After oral administration, pharmacokinetic parameters used to quantify bioavailability were near three-fold greater in female subjects than in males, with large inter-individual variations. The maximum plasma MLT concentration C(max)+/-S.D. was found at 243.7+/-124.6 pg/mL and 623.6+/-575.1 pg/mL for male and female subjects respectively, while the mean values for AUCs were 236+/-107 pg.h/mL and 701+/-645 pg.h/mL. The absolute bioavailability of MLT was from 1 to 37%: mean=8.6+/-3.9% and 16.8+/-12.7% for male and female subjects, respectively.

GDC in ruptured versus unruptured aneurysms.

We have treated 581 aneurysms in 510 patients from August 1990 to November 1998. In 247 patients the presentation was acute rupture. In 141 patients the aneurysm treated was incidental. Complications in the acute group was 10.1% morbidity with 2.8% procedure related mortality. The corresponding rates were 4.2% and 0% in the incidental group. In the incidental group all complications occurred up to 1995. In our last 91 patients there has been no morbidity or mortality. Anatomic outcomes were dependent upon aneurysm geometry in both groups. This low rate of complications when compared to the natural history for both ruptured and unruptured aneurysm favors treatment if the long-term follow-up confirms reduced longitudinal hemorrhage rates, and the aneurysm has a favorable geometry.

Embolization of dural cavernous fistulas via superior ophthalmic vein approach.

PURPOSE: To present the results of our treatment of dural cavernous sinus fistulas with surgical exposure of the superior ophthalmic vein (SOV), retrograde venous catheterization, and coil embolization of the cavernous sinus. METHODS: Twelve patients with dural cavernous sinus fistulas were treated via a retrograde transvenous SOV approach in our hospital during a 3-year period. All patients had been referred by ophthalmologists because of secondary glaucoma and decreased visual acuity. Angiography showed preferential venous drainage of the dural cavernous sinus fistulas to an enlarged ipsilateral SOV. A total of 13 SOV exposures were performed, one patient with bilateral fistulas required bilateral treatment. The vein was surgically exposed by an ophthalmologist and then catheterized. Platinum coils were delivered through a microcatheter at the fistula site and into the root of the SOV, until there was complete angiographic closure. RESULTS: Catheterization and embolization were successful in 12 of the 13 patients, with complete angiographic occlusion of the fistula. Two patients with bilateral fistulas had transient worsening of symptoms on the contralateral side. Three patients required follow-up angiography. No early complications occurred, and late complications were minor in two cases. All patients except one with long-standing symptoms recovered premorbid visual acuity. At follow-up, 11 (92%) of the 12 embolized fistulas remained occluded. CONCLUSIONS: Retrograde catheterization of the SOV and embolization of the cavernous sinus with coils is a direct, safe, and efficient way to occlude dural cavernous sinus fistulas.

Giant perimedullary arteriovenous fistulas of the spine: clinical and radiologic features and endovascular treatment.

PURPOSE: To present the clinical and radiologic features of giant perimedullary arteriovenous fistulas (GAVFs) in 12 consecutive cases and to evaluate the results of endovascular treatment. METHODS: We retrospectively reviewed the clinical and radiologic data as well as the results of balloon endovascular treatment obtained from 1980 to 1989. RESULTS: GAVFs, defined as large intradural perimedullary direct arteriovenous high-flow shunts, are revealed mainly in childhood either by subarachnoid hemorrhage or by progressive neurologic disorders. MR imaging and myelography show major vascular dilatations. The angioarchitecture of GAVFs can only be assessed by selective spinal angiography. Ten patients were treated by balloon occlusion resulting in eight anatomic cures and six good clinical results. One balloon migrated to the venous side, leading to clinical deterioration. CONCLUSION: GAVF is a special subgroup of intradural perimedullary arteriovenous fistula. The endovascular approach should be the first line of treatment, with surgery reserved for special circumstances. Nondetachable balloon occlusion is a safe and efficient method for treating GAVFs.

Disagreement between the Roche Cobas Core and Hybritech TANDEM-E PSA assays when measuring free, complexed and total serum prostate specific antigen.

A comparison of the Roche Cobas Core and Hybritech TANDEM-E PSA (prostate specific antigen) assays revealed a large difference in the reactivity of each assay to the separated free and complexed forms of serum PSA in patients with prostatic carcinoma. The Roche assay was relatively much more responsive to the free form, but the Hybritech assay was relatively more responsive to the complexed form and total serum PSA. It is possible that the adoption of a universal standard for PSA will not completely resolve the disagreement between PSA assay on individual patient samples, and the use of separate assays for the free and complexed forms may be necessary for the further clinical development of PSA as a tumour marker.

A highly sensitive assay of melatonin at the femotogram level in human plasma by gas chromatography/negative ion chemical ionization mass spectrometry.

A highly sensitive and specific assay was developed for routine analysis of melatonin at the femotogram level in human plasma. Melatonin and the deuterated internal standard [(2H4)melatonin] were measured by gas chromatography/negative ion chemical ionization mass spectrometry with methane as the reagent gas. A simple liquid-liquid extraction procedure was used to isolate the two compounds of interest from the complex biological matrix. Melatonin was converted to the fluorinated derivative with pentafluoropropionic anhydride. The mass spectrometer was tuned to monitor the very intense and stable ions at m/z 320 and 323 which were generated into the ion source by a dissociative capture process. This assay was conducted with 1 ml of plasma and the quantification limit of the method was statistically calculated as 0.5 pg ml-1. The very low relative standard deviations and mean percentages of error calculated during the within-day or between-day repeatability assays have clearly demonstrated the ruggedness of the technique for the routine quantitative measurement of melatonin in plasma. Some results on the melatonin circadian rhythm are presented to illustrate the applicability of this powerful gas chromatographic/mass spectrometric method.

Phase contrast magnetic resonance of the spinal cord preliminary results in spinal cord arterio-venous malformations.

In spite of the recent advances in neuroradiology including the CT scan and the spin-echo-magnetic resonance (MR), accurate diagnosis of arteriovenous malformations (AVMs) involving the spinal cord is still based on selective angiography. This last procedure is invasive and needs to be repeated during the follow up. Phase contrast angio MR was performed with a 0.5 Tesla unit on 12 patients with an AVM involving the spinal cord (7 intramedullary AVMs, 4 perimedullary fistulas, and 1 dural fistula with perimedullary venous drainage); 4 of these were investigated before and after treatment. Angio MR showed abnormal vascular patterns within the spinal canal in all cases, without distinguishing between arteries and veins; the nidus of the intramedullary AVMs was displayed in all cases. Angio MR provided images of the whole AVMs comparable to the angiographic pictures, in contrast to the spin-echo MR, which provided only discontinued images of the vessels. The efficient range of velocity providing images varied, according to the type of the malformation (slow for dural fistulas, rapid for intra-medullary AVMs). In the 4 patients investigated after treatment, comparison of the images obtained before and after treatment permitted assessment of the degree of occlusion of the malformation. Finally, angio MR as a complement of spin-echo MR can now be used as a reliable tool for detection of spinal cord AVMs, assessing the indication for angiography, and, furthermore, it can probably replace most of the post-operative control angiographies.(ABSTRACT TRUNCATED AT 250 WORDS)

Pyogenic parenchymatous and nidus infection after embolization of an arteriovenous malformation. An unusual complication. Case report.

Infectious complications of cerebral angiography and of therapeutic angiographic procedures are very seldom reported. The case of an infected embolized arteriovenous malformation (AVM) by staphylococcus aureus is reported. Abscess formation became manifest seven months after the endovascular procedures. Antibiotherapy was initially started after puncturing the abscess, but finally the cure of the lesion could only be obtained by radical excision of the infected and embolized AVM, as if the persisting embolization material was promoting the infection. The modalities of infection after cerebral endovascular procedures are discussed.

Phase-contrast MR angiography of vascular malformations of the spinal cord at 0.5 T.

Preliminary experience with phase-contrast magnetic resonance (MR) angiography at 0.5 T applied in 12 cases of vascular malformations of the spinal cord is reported. There were six intramedullary arteriovenous malformations (AVMs), four perimedullary fistulas, and two dural arteriovenous fistulas with perimedullary drainage, all proved with x-ray angiography. The small size of the vessels and their location within a bony structure presented a technical challenge. Serpentine vascular signal patterns were identified within the spinal canal in all cases, showing good correlation with the x-ray angiographic pattern. Relative to spin-echo images, MR angiograms allowed better visualization of the venous drainage. The nidus of intramedullary AVMs was more difficult to recognize. The ability to manipulate the velocity-encoding value allows better characterization of flow speed. The results underline the two dimensions of the phase-contrast technique, which provides both anatomic images and dynamic information about vascular malformations. MR angiography does not replace selective x-ray angiography, which is indispensable for therapeutic strategy (endovascular procedure or surgery), but it can be considered a valuable alternative to x-ray angiography during follow-up.