Secular changes in incidence and mortality associated with Staphylococcus aureus bacteraemia in Quebec, Canada, 1991-2005.

In order to examine secular changes in the incidence and mortality associated with Staphylococcus aureus bacteraemia before and after the emergence of methicillin-resistant S. aureus (MRSA), a retrospective cohort study of 815 patients with S. aureus bacteraemia was performed in the Estrie region of Quebec, Canada, between 1991 and 2005. The primary outcome was all-cause 30-day mortality. Between 1991-1993 and 2003-2005, the proportion of cases attributed to endocarditis and pneumonia increased from 4% to 11% and from 2% to 11%, respectively, while that attributed to catheter infections decreased from 49% to 17%. MRSA was almost absent in 1991-1999, but accounted for 10% and 20% of cases in 2000-2002 and 2003-2005, respectively. The population incidence of bacteraemia caused by methicillin-susceptible S. aureus (MSSA) remained stable between 1997 and 2005, while that of MRSA increased from 0 to 7.4/100 000. Risk-factors for mortality included age, co-morbidities, female gender, residence outside the city of Sherbrooke, pneumonia (OR 3.35, 95% CI 1.96-5.73) or endocarditis (OR 2.89, 95% CI 1.67-5.01) as the source, and an absence of treatment. After adjusting for confounders, patients with MRSA bacteraemia had a higher mortality rate than those with MSSA bacteraemia (OR 2.21, 95% CI 0.99-4.96, p 0.053). Mortality in patients with MSSA bacteraemia was 19% (16/83) in 1991-1993, 23% (26/113) in 1994-1996, 29% (50/173) in 1997-1999, and 28% (52/185) in 2000-2002, decreasing to 15% (28/192) in 2003-2005, which impacted on the relative mortality rates of MRSA and MSSA. MRSA did not replace, but added to, an existing stable incidence of MSSA bacteraemia.     

Effects of grade retention on academic performance and behavioral development

This study examined the controversial practice of grade retention and children's academic and behavioral adjustment using data from the Quebec Longitudinal Study of Kindergarten Children. We employed an autoregressive modeling technique to detect the impact of being held back during primary school on subsequent academic performance and behavioral development until age 12 years. The results indicate both a short- and long-term negative influence on academic performance for boys and girls. Children's anxious, inattentive, and disruptive behaviors persisted and, in some cases, worsened after grade retention. These prospective associations were long lasting and more pronounced when grade retention occurred early in primary school. Boys were more vulnerable to the negative influence of grade retention on academic performance and classroom disruptiveness. Disruptive behavior in girls was comparatively less associated with long-term consequences than boys. Nevertheless, girls experienced both short- and long-term academic performance problems in the aftermath of grade retention. Children's prosocial behavior appeared unaffected by grade retention. These results are independent of what would have been expected by the natural course of academic and behavioral development.     

A dual participation of ZAP-70 and scr protein tyrosine kinases is required for TCR-induced tyrosine phosphorylation of Sam68 in Jurkat T cells

Sam68 has been initially described as a substrate of src kinases during mitosis in fibroblasts. Recent evidence suggests that in T lymphocytes Sam68 may act as an adaptor protein and participate in the early biochemical cascade triggered after CD3 stimulation. A direct interaction between Sam68 and the two src kinases involved in T cell activation, p59^fyn and p56^lck, as well as a partnership of Sam68 with various key downstream signaling molecules, like phospholipase Cγ-1 and Grb2, has been shown. In this study we analyze the contribution of p56^lck, as well as the role of ZAP-70, the second class of protein tyrosine kinase involved in T cell activation, in Sam68 tyrosine phosphorylation in the human Jurkat T cell line. Using the src inhibitor PP1 [4-amino-5-(4-methylphenyl)7-(t-butyl) pyrazolo [3,4-d] pyrymidine] and cell variants with defective expression of p56^lck or expressing a dominant negative form of ZAP-70, we demonstrate that, while both p56^lck and ZAP-70 are dispensable for the low constitutive phosphorylation of Sam68 observed in Jurkat cells, a cooperation between the two kinases is required to increase its rapid phosphorylation observed in vivo after CD3 stimulation. We also show that recombinant forms of both p56^lck and ZAP-70 phosphorylate Sam68 in vitro. However, using CD2 stimulated cells, we observe that p56^lck activation by itself does not induce Sam68 tyrosine phosphorylation. We conclude that p59^lck and p56^lck differently participate in regulating the phosphorylation state of Sam68 in T cells and that ZAP-70 may contribute to Sam68 tyrosine phosphorylation and to the specific recruitment of this molecule after CD3 stimulation.     

Evaluation of the VITEK 2 System for Rapid Identification of Medically Relevant Gram-Negative Rods

The new VITEK 2 system (bioMérieux) was evaluated at two independent sites with the identification card for gram-negative bacilli (ID-GNB card). Of the 845 strains tested, which represented 70 different taxa belonging to either the family Enterobacteriaceae or the nonenteric bacilli, 716 (84.7%) were correctly identified at the species level. Thirty-two (3.8%) additional strains were identified to the species level after the performance of simple, rapid manual tests (oxidase, hemolysis, indole reaction, motility, and pigmentation). For 80 (9.5%) strains, these additional tests did not lead to an identification at the species level but the correct species identification was given among the organisms listed. Only 7 (0.8%) strains were misidentified, and 10 (1.2%) were not identified. Mistakes were randomly distributed over different taxa. Due to the new, more sensitive fluorescence-based technology of the VITEK 2 system, final results were available after 3 h. Since our evaluation was mainly a stress test, it is predicted that the VITEK 2 system in conjunction with the ID-GNB card would perform well under conditions of a routine clinical laboratory in identifying members of the family Enterobacteriaceae and selected species of nonenteric bacteria. This system is a promising, highly automated new tool for the rapid identification of gram-negative bacilli from human clinical specimens.     

Submaximal power output in adopted and biological siblings

Submaximal power output was determined in relative steady state on a bicycle ergometer at a heart rate of 150 beats per minute (PWC150). PWC150 was measured in 880 individuals, 9 to 26 years of age, belonging to 46 sibships of adopted sibs, 66 sibships of unrelated individuals including adoptees, 33 sibships of first-degree cousins, 225 sibships of biological sibs, 56 sibships of DZ twins and 54 sibships of MZ twins. PWC150, PWC150/kg of body weight, PWC150/kg lean body mass, PWC150/cm of height and PWC150/m2 of body surface area were submitted to analysis of variance and correlation analysis after statistical control over age and sex of subjects. Few significant resemblances were found in PWC measurements for adoptive siblings, unrelated sibs and cousins. Sibling resemblance was, however, significant for the sibships of biological sibs, and of DZ and MZ twins. Interclass correlations reached significance only in pairs of biological brothers and sisters, and in pairs of DZ and MZ twins. Estimates of total genetic effect in PWC150/kg in a population of free-living children, adolescents and young adults vary from 0.30 to 0.48. It is concluded that submaximal power output is only moderately affected by the genotype.     

Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy

The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.     

Reward-related neuronal activity during go-nogo task performance in primate orbitofrontal cortex

The orbitofrontal cortex appears to be involved in the control of voluntary, goal-directed behavior by motivational outcomes. This study investigated how orbitofrontal neurons process information about rewards in a task that depends on intact orbitofrontal functions. In a delayed go-nogo task, animals executed or withheld a reaching movement and obtained liquid or a conditioned sound as reinforcement. An initial instruction picture indicated the behavioral reaction to be performed (movement vs. nonmovement) and the reinforcer to be obtained (liquid vs. sound) after a subsequent trigger stimulus. We found task-related activations in 188 of 505 neurons in rostral orbitofrontal area 13, entire area 11, and lateral area 14. The principal task-related activations consisted of responses to instructions, activations preceding reinforcers, or responses to reinforcers. Most activations reflected the reinforcing event rather than other task components. Instruction responses occurred either in liquid- or sound-reinforced trials but rarely distinguished between movement and nonmovement reactions. These instruction responses reflected the predicted motivational outcome rather than the behavioral reaction necessary for obtaining that outcome. Activations preceding the reinforcer began slowly and terminated immediately after the reinforcer, even when the reinforcer occurred earlier or later than usually. These activations preceded usually the liquid reward but rarely the conditioned auditory reinforcer. The activations also preceded expected drops of liquid delivered outside the task, suggesting a primary appetitive rather than a task-reinforcing relationship that apparently was related to the expectation of reward. Responses after the reinforcer occurred in liquid- but rarely in sound-reinforced trials. Reward-preceding activations and reward responses were unrelated temporally to licking movements. Several neurons showed reward responses outside the task but instruction responses during the task, indicating a response transfer from primary reward to the reward-predicting instruction, possibly reflecting the temporal unpredictability of reward. In conclusion, orbitofrontal neurons report stimuli associated with reinforcers are concerned with the expectation of reward and detect reward delivery at trial end. These activities may contribute to the processing of reward information for the motivational control of goal-directed behavior.     

Measurement of 5-HIAA levels in ventricular CSF (by LCEC) and in striatum (byin vivo voltammetry) during pharmacological modifications of serotonin metabolism in the rat

Summary The relationship between the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the CSF and in the striatum has been evaluated in the rat by measuring the levels of this metabolite in ventricular CSF (by liquid chromatography coupled with electrochemical detection) and in the striatal extracellular fluid (byin vivo voltammetry) after administration of inhibitors of serotonin synthesis or degradation. Pargyline, NSD 1015 and-propyldopacetamide all caused an exponential decline of 5-HIAA in both CSF and striatum. For a given drug, the rate constants for 5-HIAA disappearance were identical in the CSF and in the striatal extracellular fluid. These results confirm the view that CSF 5-HIAA may serve as a good index of brain serotonin turnover.     

Quantitation of differential sensitivity of normal marrow myeloid progenitor cells to anthracene derivatives

The effect of 3 anthracene derivatives, mitoxantrone, ametantrone, bisantrene, on 4 normal human bone marrows, was studied using the myeloid stem cell assay developed by Pike and Robinson, in order to define to what extent this test could be used to predict the relative clinical hematologic toxicity of new anticancer agents. For the 3 drugs, an exponential relationship between colony survival and drug concentration was found, but was much steeper for mitoxantrone (slope = -195.2 ± 8.8/g/ml) than for ametantrone (slope = 5.1 ± 1.0/g/ml, p0.001) and bisantrene (slope = 7.1 ± 0.3/g/ml, p0.001). The difference of slope between ametantrone and bisantrene was of borderline significance (p0.05). The ratios of concentrations inducing a 50% growth inhibition for mitoxantrone versus bisantrene and for ametantrone versus bisantrene were close to the corresponding ratios of concentrations inducing a 90% growth inhibition. The relative in vitro toxicities reproduce very well the relative myelosuppression observed in clinical trials with mitoxantrone versus bisantrene but the results were less satisfactory for the comparison of these 2 agents with ametantrone. In addition, our data suggest that, for these 3 compounds, intrinsic myeloid progenitor sensitivity is a major determinant of leukopenia.