Study of the time course of the clinical effect of propofol compared with the time course of the predicted effect-site concentration: Performance of three pharmacokinetic-dynamic models.

BACKGROUND: In the ideal pharmacokinetic-dynamic (PK-PD) model for calculating the predicted effect-site concentration of propofol (Ce(PROP)), for any Ce(PROP), the corresponding hypnotic effect should be constant. We compared three PK-PD models (Marsh PK with Shüttler PD, Schnider PK with fixed ke0, and Schnider PK with Minto PD) in their ability to maintain a constant bispectral index (BIS), while using the respective effect-site-controlled target-controlled infusion (TCI) algorithms. METHODS: We randomized 60 patients to Group M (Marsh's model with k(e0)=0.26 min(-1)), Group S1 or Group S2 (Schnider's model with a fixed k(e0)=0.456 min(-1) or a k(e0) adapted to a fixed time-to-peak effect=1.6 min, respectively). All patients received propofol at a constant rate until loss of consciousness. The corresponding Ce(PROP), as calculated by the respective models, was set as a target for effect-site-controlled TCI. We observed BIS for 20 min. We hypothesized that BIS remains constant, if Ce(PROP) remains constant over time. RESULTS: All patients in Group M woke up, one in Group S1 and none in Group S2. In Groups S1 and S2, BIS remained constant after 11 min of constant Ce(PROP), at a more pronounced level of hypnotic drug effect than intended. CONCLUSIONS: Targeting Ce(PROP) at which patients lose consciousness with effect-site-controlled TCI does not translate into an immediate constant effect.

Comparison of contemporary EEG derived depth of anesthesia monitors with a 5 step validation process.

During the last decennium, a growing number of depth of anesthesia monitors, extracting information from the spontaneous electroencephalogram (EEG) have been developed and commercialized. The growing interest in depth of anesthesia monitoring resulted in an intensified technological progress. Innovations on both hardware and mathematical algorithms were introduced for improving the extraction of data. Because of the abundance of monitors now commercially available, it becomes increasingly important to develop a standardized reproducible methodology for comparing depth of anesthesia monitors. In this review, the authors present a strategy to compare monitors of the hypnotic component of anesthesia, based on the available literature and their own experience with validation studies. They also discuss the level of validation of the most commonly used EEG derived depth of anesthesia monitors.

The peri-operative use of intra-articular local anesthetics: a review.

Acute and chronic pain are of major concern after orthopedic surgery. The increasing trend toward day case surgery induced the development of different techniques in postoperative pain control. One commonly used strategy in pain management after knee and shoulder joint surgery is the intra-articular (IA) use of local anesthetics (LA). Recent attention has been drawn to the possible toxicity on chondrocytes of local anesthetics. The aim of this manuscript is to evaluate and compare through literature review the existing evidence on the clinical use and possible adverse effects of intra-articular injection of local anesthetics peri-operatively.

Cloning of the cDNA encoding human platelet CD36: comparison to PCR amplified fragments of monocyte, endothelial and HEL cells.

Glycoprotein CD36, also known as GPIIIb or GPIV, is a major platelet glycoprotein that bears the newly identified Naka alloantigen. The aim of this study was to clone platelet CD36 and investigate other forms of CD36-cDNA present in monocytes, endothelial and HEL cells. RNA from above mentioned cells were reverse transcribed (RT), using specific primers for CD36, and amplified by the polymerase chain reaction (PCR) technique. Sequencing the different amplified platelet derived cDNA fragments, spanning the whole coding and flanking regions, showed the near identity between platelet and CD36-placenta cDNA. Platelet CD36-cDNA cross-hybridized, in Southern blots, with RT-PCR amplified cDNA originating from monocytes, endothelial and HEL cells. However, monocytes showed a RT-PCR amplified cDNA fragment (561 bp) that was present in platelets and placenta but not on endothelial on HEL-cells. Northern blot analysis of platelet RNA hybridized with placenta CD36 indicated the presence of a major (1.95 kb) and a minor (0.95 kb) transcript. The 1.95 kb transcript was the only one observed on Northern blots of monocytes, endothelial and HEL cells. These results indicate that the structure of CD36 expressed in platelets is similar, with the exception of the 3' flanking region, to that of placenta. Differences in apparent molecular weight between CD36 and CD36-like glycoproteins may be due to post-translational modifications.

Training to deeper compression depth reduces shallow compressions after six months in a manikin model.

INTRODUCTION: Studies show that students, trained to perform compressions between 40 and 50mm deep, often do not achieve sufficient depth at retention testing. We hypothesized that training to achieve depths >50mm would decrease the proportion of students with depth <40mm after 6 months, compared to students trained to a depth interval of 40-50mm. METHODS: A basic life support (BLS) self-learning station was attended by 190 third year medicine students. They were first offered the possibility to refresh their skills, following the instructions of a 15min abbreviated Mini Anne™ video (Laerdal, Norway) using a full size torso and a face shield. This was followed by further training using Resusci Anne Skills Station™ software (Laerdal, Norway). Voice feedback was provided according to randomisation to a standard group (SG) 40-50mm and a deeper group (DG) >50mm. Quality of compressions was tested after 6 months. RESULTS: The SG and DG groups consisted of 90 (67% female) and 100 (58% female) participants respectively. At the end of training, all students reached the target depth without overlap between groups. After 6 months, the proportion of students achieving a depth <40mm was 26/89 (29%) in the SG vs. 12/89 (14%) in the DG (P=0.01). The proportion of students with a depth >50mm was 5/89 (6%) for the SG and 44/89 (49%) in the DG (P<0.001). CONCLUSIONS: The educational strategy to train students to a deeper depth, reduced shallow compressions 6 months after training.

[Radioiodine therapy in hyperthyroidism: reliability of a long-term follow-up scheme for the diagnosis and treatment of hyperthyroidism based on the family physician and on a central registry]. / Radiojodtherapie bei Hyperthyreose: Zuverlässigkeit eines auf dem Hausarzt und einem zentralen Register basierenden Nachkontrollschemas zur Erfassung und Behandlung der Hypothyreose.

We assessed the reliability of a follow-up scheme for radioiodine-treated patients which involved the general practitioner after the first year, leaving to the center only the operation of a central recall registry and the analysis of mailed blood samples and simple questionnaires. The analysis of 238 patients followed up for 3-6 years showed that the scheme was equal or superior to follow-up rates of published systems in Switzerland which rely on regular recalls of the patients to the center. However, the excellent follow-up rates published with similar systems in Great Britain were not quite achieved and efforts will be needed to diminish the number of patients lost to follow-up. Contrary to the experience of other authors, our laboratory results did not allow us to single out a group of patients with low likelihood of developing hypothyroidism and in whom follow-up examinations could be spaced at longer intervals. Reversing our current practice, we now recommend that hypothyroid patients be left on our registry once they are on replacement therapy with thyroxine. Examination of this patient group has revealed that 27% are undersubstituted, albeit only to a borderline degree in most cases.

Glycoprotein Ib beta is the only phosphorylated major membrane glycoprotein in human platelets.

Platelets were metabolically labelled with 32P and the phosphoproteins examined by two-dimensional non-reduced/reduced gel electrophoresis and isoelectric-focusing/gel electrophoresis. Comparison with similar separations of surface-labelled platelets showed that the only major glycoprotein which is phosphorylated is the beta-subunit of glycoprotein Ib, indicating that this subunit contains a cytoplasmic segment. The identification was confirmed using immunoblotting with an antibody to the beta-subunit. Phosphoserine was the principal phosphorylation site, with some phosphothreonine, but phosphotyrosine was absent. No quantitative or qualitative differences could be detected in the phosphorylation of glycoprotein Ib beta from resting or activated platelets. These results exclude changes in phosphorylation of the major platelet membrane glycoproteins as a method of signal transmission by these receptors.

The molecular genetic basis of Glanzmann's thrombasthenia in a gypsy population in France: identification of a new mutation on the alpha IIb gene.

Glanzmann's thrombasthenia is a rare inherited bleeding disorder caused by a qualitative or quantitative defect of platelet alpha IIb beta 3. We describe here a new mutation that is the molecular genetic basis of Glanzmann's thrombasthenia in two gypsy families. Our investigation was focused on the alpha IIb gene as a result of biochemical and immunologic analysis of patients' platelets showing undetectable alpha IIb but residual beta 3 levels. The entire alpha IIb cDNA was polymerase chain reaction (PCR) amplified using patients platelet RNA. Sequence analysis showed an 8-bp deletion located at the 3' end of exon 15. This deletion causes a reading-frame shift leading to a premature stop codon and the synthesis of a severely truncated form of alpha IIb. Genomic DNA study showed a G-->A substitution, the Gypsy mutation, at the splice donor site of intron 15. This mutation results in an abnormal splicing occurring at an alternative donor site located 8 bp upstream from the mutation. Based on those results, an allele-specific PCR analysis was developed to allow a rapid identification of the mutation in patients and potential carriers of the gypsy community. This PCR analysis can also be used for genetic counseling and antenatal diagnosis.

The vitronectin receptor (alpha v beta 3) is implicated, in cooperation with P-selectin and platelet-activating factor, in the adhesion of monocytes to activated endothelial cells.

In this study we have investigated the presence on endothelial cells of potential glycoprotein receptors, other than P-selectin, which are involved in the adhesion of monocytes at the early stages of activation. We report that the majority of cells binding to thrombin-activated endothelial cells from a peripheral blood mononuclear cell (PBMC) preparation are monocytes. The adhesion of PBMC to thrombin-activated, but not resting, endothelial cells was inhibited (66%) by a monoclonal antibody (mAb) directed against alpha v beta 3. Elutriated monocytes or a monocytic cell line (U937) were also inhibited by this antibody, its F(ab)'2 fragments and three other anti-(alpha v beta 3) mAbs. alpha v beta 3 isolated from endothelial-cell lysates significantly inhibited the adhesion of monocytes and U937 cells to endothelial cells. A peptide motif (RGDF) known to interact with alpha v beta 3 inhibited U937 cell adhesion to activated endothelial cells by 53%. Finally, an anti-(P-selectin) mAb (LYP20) or a platelet-activating factor (PAF)-receptor antagonist (WEB 2086) inhibited monocyte adhesion to activated endothelial cells. This study shows for the first time that alpha v beta 3 is implicated, in addition to P-selectin and PAF, in the adhesion of monocytes to activated endothelial cells.

Intermittent exposure to doxorubicin in vitro selects for multifactorial non-P-glycoprotein-associated multidrug resistance in RPMI 8226 human myeloma cells.

The purpose of the present study was to evaluate whether intermittent exposure to a constant dose of doxorubicin selects for multidrug resistance (MDR) in RPMI 8226 human myeloma cells and, if so, to determine the molecular mechanism. In an attempt to approximate clinical doxorubicin treatment in vitro, cells were exposed to a fixed dose of doxorubicin for 4 d alternating with growth in drug-free medium for 17 d. An MDR subline emerged, termed 8226/DOXint5, which was 3-4-fold resistant to doxorubicin, etoposide and m-AMSA, and 1.6-fold resistant to vincristine. Sensitivity to docetaxel, melphalan and cisplatin was normal. Verapamil normalized vincristine sensitivity but had little effect on resistance to the other agents. Cellular uptake and retention of daunorubicin and vincristine were reduced by approximately 10%. The 8226/DOXint5 cells showed diminished DNA topoisomerase IIalpha expression and increased expression of the multidrug resistance protein MRP. Expression of MDR1/P-glycoprotein was not detected. Immunostaining showed 70% of the cells to over-express the lung-resistance protein LRP. This new MDR myeloma cell line may prove to be a useful model for the development of strategies to overcome low-level, multifactorial MDR, which might be a common phenomenon in clinical myeloma treated with doxorubicin.