Comparison of the effects of racemic bupivacaine, levobupivacaine, and ropivacaine on ventricular conduction, refractoriness, and wavelength: an epicardial mapping study

BACKGROUND: The study was designed to compare the effects of equimolar concentrations of racemic bupivacaine, levobupivacaine, and ropivacaine on ventricular conduction, anisotropy, duration and homogeneity of refractoriness, and wavelengths, and to provide a potency ratio for effects on conduction velocity. METHODS: Isolated frozen rabbit hearts (which leave a thin layer of surviving epicardial muscle) were treated with 0.1, 1, and 10 mum racemic bupivacaine, levobupivacaine, or ropivacaine. Left ventricular longitudinal and transverse conduction velocities, anisotropic ratio, minimum pacing cycle length, use dependency, duration and dispersion of ventricular effective refractory period, and wavelengths were studied. A high-resolution mapping system was used for data acquisition. In addition to two-way analysis of variance for repeated measures, data for conduction velocities were fitted simultaneously using a nonlinear mixed-effect modeling program to allow intergroup comparison. RESULTS: Each agent induced a concentration- and use-dependent slowing of conduction velocities, with no change of the anisotropic ratio. The use-dependent effect of levobupivacaine is similar to that of racemic bupivacaine concerning longitudinal conduction velocity. Fitting of conduction velocities provided a racemic bupivacaine to levobupivacaine and to ropivacaine ratio of 1:1.38 for concentration effect at 1,000-ms pacing cycle length, and 1:0.74 for use-dependent effect at 600-ms pacing cycle length. Racemic bupivacaine and levobupivacaine prolonged the ventricular effective refractory period, whereas ropivacaine did not. No dispersion in ventricular effective refractory period values occurred. All three agents induced significant decreases in wavelengths. This effect was not different among groups. CONCLUSIONS: Differences among racemic bupivacaine, levobupivacaine, and ropivacaine at equimolar concentrations are mainly caused by the use-dependent effects on conduction velocities and the concentration-dependent effects on ventricular effective refractory period. Therefore, one must take into account the corresponding pacing rates when comparing the potency ratios of local anesthetics.     

Impact of parental relationships in maximum lod score affected sib-pair method

Many studies are done in small isolated populations and populations where marriages between relatives are encouraged. In this paper, we point out some problems with applying the maximum lod score (MLS) method (Risch, [1990] Am. J. Hum. Genet. 46:242-253) in these populations where relationships exist between the two parents of the affected sib-pairs. Characterizing the parental relationships by the kinship coefficient between the parents (f), the maternal inbreeding coefficient (alpha(m), and the paternal inbreeding coefficient (alpha(p)), we explored the relationship between the identity by descent (IBD) vector expected under the null hypothesis of no linkage and these quantities. We find that the expected IBD vector is no longer (0.25, 0.5, 0.25) when f, alpha(m), and alpha(p) differ from zero. In addition, the expected IBD vector does not always follow the triangle constraints recommended by Holmans ([1993] Am. J. Hum. Genet. 52:362-374). So the classically used MLS statistic needs to be adapted to the presence of parental relationships. We modified the software GENEHUNTER (Kruglyak et al. [1996] Am. J. Hum. Genet. 58: 1347-1363) to do so. Indeed, the current version of the software does not compute the likelihood properly under the null hypothesis. We studied the adapted statistic by simulating data on three different family structures: (1) parents are double first cousins (f=0.125, alpha(m)=alpha(p)=0), (2) each parent is the offspring of first cousins (f=0, alpha(m)=alpha(p)=0.0625), and (3) parents are related as in the pedigree from Goddard et al. ([1996] Am. J. Hum. Genet. 58:1286-1302) (f=0.109, alpha(m)=alpha(p)=0.0625). The appropriate threshold needs to be derived for each case in order to get the correct type I error. And using the classical statistic in the presence of both parental kinship and parental inbreeding almost always leads to false conclusions.     

Carcinogenesis and translational controls: TACC1 is down-regulated in human cancers and associates with mRNA regulators

The three human TACC genes encode a family of proteins that are suspected to play a role in carcinogenesis. Their function is not precisely known; a Xenopus TACC protein called Maskin is involved in translational control, while the Drosophila D-TACC associates with microtubules and centrosomes. We have characterized the human TACC1 gene and its products. The TACC1 gene is located in region p12 of chromosome 8; its mRNA is ubiquitously expressed and encodes a protein with an apparent molecular mass of 125 kDa, which is cytoplasmic and mainly perinuclear. We show that TACC1 mRNA gene expression is down-regulated in various types of tumors. Using immunohistochemistry of tumor tissue-microarrays and sections, we confirm that the level of TACC1 protein is down-regulated in breast cancer. Finally, using the two-hybrid screen in yeast, GST pull-downs and co-immunoprecipitations, we identified two potential binding partners for TACC1, LSM7 and SmG. They constitute a conserved subfamily of Sm-like small proteins that associate with U6 snRNPs and play a role in several aspects of mRNA processing. We speculate that down-regulation of TACC1 may alter the control of mRNA homeostasis in polarized cells and participates in the oncogenic processes.     

De la tautologie psychotique

This study centres on the question of psychotic tautologies as found in cases of morbid rationalism and morbid geometrism (Minkowski). The study concentrates on the writings of a psychotic psychiatrist, François Klein M.D., his work is an orgy of identifications based, to a high degree, on the logic of identity ; this is seen as an opening towards a clearer understanding of the structure that produces true psychosis. The authors argue that the tautology is a kind of « meeting point » a « launch-pad » that introduces unwarranted extrapolation. In other words the tautology as an extreme of morbid rationalism opens towards a paraphrenic reconstruction. This of course is in harmony with Freud’s thinking.     

Need for closure and jumping-to-conclusions in delusion-prone individuals

Members of the general population were screened for delusion-proneness using the Peters et al. Delusions Inventory (PDI). Two groups were formed from the participants who scored in the upper and lower quartiles of the PDI and compared on a probability judgment task and on the Need for Closure scale (NFC). The study investigated whether the "jump-to-conclusions" (JTC) reasoning bias, characteristic of deluded participants, could be found in delusion-prone individuals. NFC was investigated as a motivational factor that may correlate with this reasoning bias. Evidence for the existence of the data-gathering, but not the probability judgment, part of the JTC reasoning bias was found in the delusion-prone individuals. This group also scored significantly higher on the NFC scale. As the data-gathering reasoning bias was found in delusion-prone individuals this suggests that it may be involved in the formation, rather than merely the maintenance, of delusional beliefs.     

C-peptide, IGF-I, sex-steroid hormones and adiposity: a cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC)

Objectives: The risk of some cancers is positively associated with body weight, which may influence circulating levels of sex-steroid hormones, insulin and IGF-I. Interrelationships between these hormones and the associations with adiposity were evaluated in healthy women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods: A cross-sectional analysis was performed on anthropometric and hormonal data from 743 pre- and 1217 postmenopausal women. Body mass index (BMI) and waist circumference were used as indicators of adiposity. C-peptide, Insulin Growth Factor (IGF)-I, Insulin Growth Factor binding protein (IGFBP)-3, androgens, estrogens and sex hormone binding globulin (SHBG) were measured by immunoassays; free sex steroid concentrations were calculated.Results: BMI and waist circumference were positively correlated with estrogens in postmenopausal women and with C-peptide, free testosterone and inversely with SHBG in all women. C-peptide and IGF-I were inversely correlated with SHBG, and positively with free sex steroids in postmenopausal women. IGF-I was positively associated with postmenopausal estrogens and androgen concentrations in all women.Conclusions: Sex-steroid concentrations appear to be regulated along several axes. Adiposity correlated directly with estrogens in postmenopausal women and with insulin, resulting in lower SHBG and increased levels of free sex steroids. Independent of adiposity and insulin, IGF-I was associated with decreased SHBG levels, and increased concentrations of androgens and postmenopausal estrogens.     

Drug related falls: a study in the French Pharmacovigilance database

OBJECTIVE: To investigate the risk of falls associated with drugs among the French population using data reported to the French spontaneous reporting system and recorded in the French Pharmacovigilance database. METHODS: All cases including a fall were searched in the French Pharmacovigilance database between 1995 and 1999. Drugs involved and characteristics of patients were investigated. In a second step, we estimated the risk associated with psychotropic and cardiovascular drugs in a case/non case comparison, where cases were reports including a fall and non cases all other reports. This risk was estimated by calculation of crude and age and gender adjusted reporting odds ratios (ROR). RESULTS: During this period, 328 reports including a fall were reported (0.4% of the database). Patients were female in 70%. Mean age was 76 +/- 18 years. Comparisons between cases and non cases showed that cases were more likely to be women (OR: 1.9; 95% confidence interval (CI) [1.5-2.4]) and older. After adjustment on age and gender, falls remained significantly associated with exposure to benzodiazepines (4.7 [3.7-5.9]), imipraminic antidepressants (3.6 [2.5-5.1]), serotonin reuptake inhibitor (SRI) antidepressants (2.2 [1.5-3.1]) or nitrates (1.9 [1.2-2.8]). CONCLUSION: This study confirms that taking psychotropic drugs strongly increases the risk of falls. The role of cardiovascular drugs (except nitrates) remains not significant when confounding factors are taken into account. According to the very high prevalence of psychotropic drug use in the French elderly, further study are needed to investigate the relative effect of some drugs on falls, like for example SRIs or short acting benzodiazepines.     

Alkylation of beta-tubulin on Glu 198 by a microtubule disrupter

We have shown that beta-tubulin was alkylated by a microtubule disrupter, N-4-iodophenyl-N'-(2-chloroethyl)urea (ICEU), on a glutamic acid residue at position 198 and not on the previously proposed reactive cysteine 239. ICEU belongs to the 4-substituted-phenyl-N'-(2-chloroethyl) urea class that alkylates mainly cellular proteins. Previous studies have shown that the tert-butyl (tBCEU) and iodo (ICEU) derivatives induce microtubule disruption because of beta-tubulin alkylation. tBCEU was supposed to bind covalently to cysteine 239 of beta-tubulin, but this binding site was not clearly confirmed (Cancer Res 60:985-992, 2000). We have isolated and analyzed beta-tubulin after two-dimensional gel electrophoresis of proteins from B16 cells incubated with ICEU. Alkylated beta-tubulin had a lower apparent molecular weight and a more basic isoelectric point than the unmodified protein. Labeled N-4-[125I]CEU was effectively bound to the modified beta-tubulin but using matrix-assisted laser desorption ionization/time-of-flight mass spectrometry, we demonstrated that none of the cysteine residues of beta-tubulin was linked to the alkylating agent. In contrast, peptide masses at m/z 4883 and 1792 in trypsin or Asp-N digestions of beta-tubulin confirmed binding of iodophenylethylureido moiety to peptides [175-213] or [197-208] respectively. Fragmentation analyses by electrospray mass spectrometry using triply charged ions of peptide [175-213] identified a glutamic acid at position 198 as target for alkylation via an ester bond with ICEU. This amino acid located in the intermediate domain of the beta-tubulin should play an essential role in the conformational structure necessary for the interaction between dimers in the protofilament.     

Antibacterial activity of clonidine and neostigmine in vitro

We conducted an in vitro study to investigate the antibacterial activity of clonidine and neostigmine on common microorganisms encountered during infectious complications after regional anesthesia. Standardized suspensions of Staphylococcus aureus, Staphylococcus epidermidis and Escherichia coli were incubated during 1, 3, 6, and 24 h at 37 degrees C with concentrations of 37.5, 75, and 150 microg/mL of clonidine and 125, 250, and 500 microg/mL of neostigmine. After 24 h incubation at 37 degrees C, the colony counts were compared by two-way analysis of variance. The mean colony counts for S. aureus decreased significantly from control as the exposure to clonidine increased (P < 0.05), with a approximately 100% kill at 6 h for the largest concentration (150 microg/mL) and at 24 h for the intermediate concentration (75 microg/mL). Similar results were observed for S. epidermidis, with a approximately 100% kill at 6 h for the largest concentrations (75 and 150 microg/mL). No bactericidal activity of clonidine was observed for E. coli and no bactericidal activity of neostigmine was observed for any of the tested strains. In the conditions of this experiment, clonidine, but not neostigmine, exhibited a concentration-dependent and time-dependent bactericidal activity in vitro on the microorganisms most frequently encountered in infectious complications after regional anesthesia.