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.

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.

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.

The development of a catechol enzyme electrode and its possible use for the diagnosis and monitoring of neural crest tumours.

A catechol enzyme electrode is described, in which a Clark-type oxygen electrode is coupled to immobilised polyphenol oxidase in albumin cross linked with glutaraldehyde on a dialysis membrane. Electrode calibration, response time, pH response profile, stability, detection limit and selectivity are evaluated and the feasibility of using the electrode for the measurement of catecholamines in the urine of patients with neural crest tumours is assessed.

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.

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.

Auditing quality control procedures in a chemical pathology laboratory--a multiple regression analysis.

We undertook a retrospective analysis of the monthly test rejection rates and the monthly external quality assessment scheme performance indices for our laboratory's two automated analysers, and examined the association of these variables with measures of laboratory workload, manpower, staff training, instrument servicing, seasonal and temporal factors and changes of calibration, method and assigned internal quality control values. Using multiple linear regression and stepwise multiple linear regression, we found that test rejection rates differed significantly between instruments, and were highest on the instrument performing the widest variety and lowest volume of tests. On that instrument, rejection rates were significantly associated with the introduction of new staff and laboratory manpower levels, and also showed a highly significant trend upwards over the study period, independent of the effects of the other variables examined. External quality assessment scheme performance indices showed small trends over the study period. They were not related to the test rejection rates on either analyser but also showed a significant association with the introduction of new staff and a small but significant association with laboratory workload. We conclude that the training and introduction of new staff and decreased laboratory manpower levels may significantly increase the level of test rejection, and adherence to appropriate quality control protocols effectively maintains the quality of the laboratory's results, but may not be completely successful in filtering out the effects of some assignable causes of variation in test results. It is suggested that clinical laboratories use the statistical approach adopted here to identify factors which may be adversely affecting quality performance and running costs and to provide evidence that quality control procedures are both cost- and quality-effective.

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.

Percutaneous automated lumbar nucleotomy.

The results of percutaneous automated lumbar nucleotomy in the treatment of lumbar disc herniation were assessed in a series of 39 patients. The technique consists of mechanical decompression of the herniated intervertebral disc without total excision. Only one-space discs were treated by this method. Sciatica was the predominant clinical symptom in 30 cases, and lumbar pain in 9 cases. Good to very good results were obtained in 70% of patients with sciatica and in 55% of patients with lumbar pain. After 4 cases of nucleotomy performed after failure of nucleolysis were excluded, the proportion of very good results rose to 77% in sciatica. Conversely, it seems that a number of failed nucleotomies can be treated by nucleolysis. Nucleotomy is very well tolerated and deserves to be used as first-line treatment of single and radiologically well documented lumbar disc herniations.

[Percutaneous automated lumbar nucleotomy]. / Nucléotomie lombaire percutanée automatisée.

The results of percutaneous automated lumbar nucleotomy in the treatment of lumbar disc herniation were assessed in a series of 39 patients. The technique consists of mechanical decompression of the herniated intervertebral disc without total excision. Only one-space discs were treated by this method. Sciatica was the predominant clinical symptom in 30 cases, and lumbar pain in 9 cases. Good to very good results were obtained in 70% of patients with sciatica and in 55% of patients with lumbar pain. After 4 cases of nucleotomy performed after failure of nucleolysis were excluded, the proportion of very good results rose to 77% in sciatica. Conversely, it seems that a number of failed nucleotomies can be treated by nucleolysis. Nucleotomy is very well tolerated and deserves to be used as first-line treatment of single and radiologically well documented lumbar disc herniations.

[Giant intracranial aneurysm. Elective endovascular treatment using metallic coils]. / Anévrysmes géants intracrâniens. Traitement endovasculaire électif par des spires métalliques.

The authors present nine cases of giant aneurysm treated endovascularly by obliteration of the aneurysm lumen using platinum coils. Three aneurysms were located on the anterior circulation and six on the vertebrobasilar system. Presenting symptoms were mass effect in five cases and subarachnoid hemorrhage in four. Total occlusion of the aneurysms was achieved in four patients and partial occlusion in five. On follow-up (15 months), there was one repermeation and one neo-aneurysm. Both of these cases were retreated with placement of additional coils. All patients who presented with a mass effect had improvement of their symptoms (two after transient aggravation). Two patients died: one partially treated from hemorrhage, and the other from M.C.A. infarct after surgical clipping of the aneurysm. One technical complication included a lost coil which did not result in any angiographic or clinical change. One year follow-up angiographies show a permanent stable occlusion induced by coils. This technique should be considered as an option when treating giant non surgical aneurysm.

[Endovascular treatment of intracranial aneurysms. Value and prospects based on a series of 92 cases]. / Traitement endovasculaire des anévrysmes intracrâniens. Intérêt et perspective d'après une série de 92 cas.

Endovascular treatment of intracranial aneurysms is a recent technique which needs to be evaluated in large series. From 1978 to 1988, 92 cases of aneurysms were balloon-treated at Lariboisière Hospital either by parent vessel occlusion (O.V.P.) (N = 48) or by selective obliteration (O.S.A.). Treatment in all but 5 cases was performed 3 weeks after S.A.H. since the main reason for choosing endovascular technique was contraindication of early surgery. Giant aneurysms account for 31 cases, vertebro-basilar for 38 and cavernous carotid for 27. In O.V.P. group, there were 17 patients referred after subarachnoid hemorrhage and 30 after tumoral symptoms, while in O.S.A. group, 30 bled and 5 presented with oculomotor palsies. Results in the O.V.P. group are good with 8% morbidity and mortality. In O.S.A., they are worse: 16% (morbidity and mortality) and 22% of secondary balloon deflation; however, because of the features of these aneurysms (size and location), the results seem quite acceptable. Endovascular treatment of intracranial aneurysms is a promising technique which should already replace parent vessel ligation when indicated, and progressively supplant surgical clipping when the remaining technical problems are resolved.

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.

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.