Genes involved in the astrocyte-neuron lactate shuttle (ANLS) are specifically regulated in cortical astrocytes following sleep deprivation in mice.

STUDY OBJECTIVES: There is growing evidence indicating that in order to meet the neuronal energy demands, astrocytes provide lactate as an energy substrate for neurons through a mechanism called "astrocyte-neuron lactate shuttle" (ANLS). Since neuronal activity changes dramatically during vigilance states, we hypothesized that the ANLS may be regulated during the sleep-wake cycle. To test this hypothesis we investigated the expression of genes associated with the ANLS specifically in astrocytes following sleep deprivation. Astrocytes were purified by fluorescence-activated cell sorting from transgenic mice expressing the green fluorescent protein (GFP) under the control of the human astrocytic GFAP-promoter. DESIGN: 6-hour instrumental sleep deprivation (TSD). SETTING: Animal sleep research laboratory. PARTICIPANTS: Young (P23-P27) FVB/N-Tg (GFAP-GFP) 14Mes/J (Tg) mice of both sexes and 7-8 week male Tg and FVB/Nj mice. INTERVENTIONS: Basal sleep recordings and sleep deprivation achieved using a modified cage where animals were gently forced to move. MEASUREMENTS AND RESULTS: Since Tg and FVB/Nj mice displayed a similar sleep-wake pattern, we performed a TSD in young Tg mice. Total RNA was extracted from the GFP-positive and GFP-negative cells sorted from cerebral cortex. Quantitative RT-PCR analysis showed that levels of Glut1, α-2-Na/K pump, Glt1, and Ldha mRNAs were significantly increased following TSD in GFP-positive cells. In GFP-negative cells, a tendency to increase, although not significant, was observed for Ldha, Mct2, and α-3-Na/K pump mRNAs. CONCLUSIONS: This study shows that TSD induces the expression of genes associated with ANLS specifically in astrocytes, underlying the important role of astrocytes in the maintenance of the neuro-metabolic coupling across the sleep-wake cycle.

Gentamicin Improves the Activities of Daptomycin and Vancomycin against Enterococcus faecalis In Vitro and in an Experimental Foreign-Body Infection Model.

For enterococcal implant-associated infections, the optimal treatment regimen has not been defined. We investigated the activity of daptomycin, vancomycin, and gentamicin (and their combinations) against Enterococcus faecalis in vitro and in a foreign-body infection model. Antimicrobial activity was investigated by time-kill and growth-related heat production studies (microcalorimetry) as well as with a guinea pig model using subcutaneously implanted cages. Infection was established by percutaneous injection of E. faecalis in the cage. Antibiotic treatment for 4 days was started 3 h after infection. Cages were removed 5 days after end of treatment to determine the cure rate. The MIC, the minimal bactericidal concentration (MBC) in the logarithmic phase, and the MBC in the stationary phase were 1.25, 5, and >20 μg/ml for daptomycin, 1, >64, and >64 μg/ml for vancomycin, and 16, 32, and 4 μg/ml for gentamicin, respectively. In vitro, gentamicin at subinhibitory concentrations improved the activity against E. faecalis when combined with daptomycin or vancomycin in the logarithmic and stationary phases. In the animal model, daptomycin cured 25%, vancomycin 17%, and gentamicin 50% of infected cages. In combination with gentamicin, the cure rate for daptomycin increased to 55% and that of vancomycin increased to 33%. In conclusion, daptomycin was more active than vancomycin against adherent E. faecalis, and its activity was further improved by the addition of gentamicin. Despite a short duration of infection (3 h), the cure rates did not exceed 55%, highlighting the difficulty of eradicating E. faecalis from implants already in the early stage of implant-associated infection.

Behavioral phenotyping of glutathione-deficient mice: Relevance to schizophrenia and bipolar disorder.

Redox-dysregulation represents a common pathogenic mechanism in schizophrenia (SZ) and bipolar disorder (BP). It may in part arise from a genetically compromised synthesis of glutathione (GSH), the major cellular antioxidant and redox-regulator. Allelic variants of the genes coding for the rate-limiting GSH synthesizing enzyme glutamate-cysteine-ligase modifier (GCLM) and/or catalytic (GCLC) subunit have been associated with SZ and BP. Using mice knockout (KO) for GCLM we have previously shown that impaired GSH synthesis is associated with morphological, functional and neurochemical anomalies similar to those in patients. Here we asked whether GSH deficit is also associated with SZ- and BP-relevant behavioral and cognitive anomalies. Accordingly, we subjected young adult GCLM-wildtype (WT), heterozygous and KO males to a battery of standard tests. Compared to WT, GCLM-KO mice displayed hyperlocomotion in the open field and forced swim test but normal activity in the home cage, suggesting that hyperlocomotion was selective to environmental novelty and mildly stressful situations. While spatial working memory and latent inhibition remained unaffected, KO mice showed a potentiated hyperlocomotor response to an acute amphetamine injection, impaired sensorymotor gating in the form of prepulse inhibition and altered social behavior compared to WT. These anomalies resemble important aspects of both SZ and the manic component of BP. As such our data support the notion that redox-dysregulation due to GSH deficit is implicated in both disorders. Moreover, our data propose the GCLM-KO mouse as a valuable model to study the behavioral and cognitive consequences of redox dysregulation in the context of psychiatric disease.

Efficacy of daptomycin in implant-associated infection due to methicillin-resistant Staphylococcus aureus: importance of combination with rifampin.

Limited treatment options are available for implant-associated infections caused by methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). We compared the activity of daptomycin (alone and with rifampin [rifampicin]) with the activities of other antimicrobial regimens against MRSA ATCC 43300 in the guinea pig foreign-body infection model. The daptomycin MIC and the minimum bactericidal concentration in logarithmic phase and stationary growth phase of MRSA were 0.625, 0.625, and 20 microg/ml, respectively. In time-kill studies, daptomycin showed rapid and concentration-dependent killing of MRSA in stationary growth phase. At concentrations above 20 microg/ml, daptomycin reduced the counts by >3 log(10) CFU/ml in 2 to 4 h. In sterile cage fluid, daptomycin peak concentrations of 23.1, 46.3, and 53.7 microg/ml were reached 4 to 6 h after the administration of single intraperitoneal doses of 20, 30, and 40 mg/kg of body weight, respectively. In treatment studies, daptomycin alone reduced the planktonic MRSA counts by 0.3 log(10) CFU/ml, whereas in combination with rifampin, a reduction in the counts of >6 log(10) CFU/ml was observed. Vancomycin and daptomycin (at both doses) were unable to cure any cage-associated infection when they were given as monotherapy, whereas rifampin alone cured the infections in 33% of the cages. In combination with rifampin, daptomycin showed cure rates of 25% (at 20 mg/kg) and 67% (at 30 mg/kg), vancomycin showed a cure rate of 8%, linezolid showed a cure rate of 0%, and levofloxacin showed a cure rate of 58%. In addition, daptomycin at a high dose (30 mg/kg) completely prevented the emergence of rifampin resistance in planktonic and adherent MRSA cells. Daptomycin at a high dose, corresponding to 6 mg/kg in humans, in combination with rifampin showed the highest activity against planktonic and adherent MRSA. Daptomycin plus rifampin is a promising treatment option for implant-associated MRSA infections.

Utilitarisme et christianisme: une triple mise en perspective

L'auteur esquisse la relation de l'utilitarisme et du christianisme sous l'angle triple des rapports entre le bien et le salut, le sacrifice et le sujet, la souffrance réduite ou affrontée. Le trépied ainsi proposé ne constitue pas une cage de fer, à laquelle toute comparaison et toute lecture devraient se soumettre ou se refuser, mais seulement une possible structure de dialogue et de débat, devant faciliter et fructifier l'interpellation réciproque de la morale utilitariste et de l'éthique chrétienne.

Repair of tracheomalacia with inflammatory defect and mediastinitis.

We describe a novel repair of an anterior inflammatory tracheal defect with mediastinitis, which occurred after external tracheal suspension of localized intrathoracic tracheomalacia. The malacic tracheal segment of 4-cm length containing the inflammatory tracheal defect was noncircumferentially resected. A temporary endotracheal silicone stent was introduced, and the trachea was closed by a pedicled pectoralis muscle flap reinforced with an embedded rib segment. Retrieval of the stent 5 months postoperatively resulted in a re-epithelialized, persistently stable, noncollapsible tracheal segment that showed the same diameter and configuration as the nonreconstructed part of the trachea.

High activity of Fosfomycin and Rifampin against methicillin-resistant staphylococcus aureus biofilm in vitro and in an experimental foreign-body infection model.

Increasing antimicrobial resistance reduces treatment options for implant-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the activity of fosfomycin alone and in combination with vancomycin, daptomycin, rifampin, and tigecycline against MRSA (ATCC 43300) in a foreign-body (implantable cage) infection model. The MICs of the individual agents were as follows: fosfomycin, 1 μg/ml; daptomycin, 0.125 μg/ml; vancomycin, 1 μg/ml; rifampin, 0.04 μg/ml; and tigecycline, 0.125 μg/ml. Microcalorimetry showed synergistic activity of fosfomycin and rifampin at subinhibitory concentrations against planktonic and biofilm MRSA. In time-kill curves, fosfomycin exhibited time-dependent activity against MRSA with a reduction of 2.5 log10 CFU/ml at 128 × the MIC. In the animal model, planktonic bacteria in cage fluid were reduced by <1 log10 CFU/ml with fosfomycin and tigecycline, 1.7 log10 with daptomycin, 2.2 log10 with fosfomycin-tigecycline and fosfomycin-vancomycin, 3.8 log10 with fosfomycin-daptomycin, and >6.0 log10 with daptomycin-rifampin and fosfomycin-rifampin. Daptomycin-rifampin cured 67% of cage-associated infections and fosfomycin-rifampin cured 83%, whereas all single drugs (fosfomycin, daptomycin, and tigecycline) and rifampin-free fosfomycin combinations showed no cure of MRSA cage-associated infections. No emergence of fosfomycin resistance was observed in animals; however, a 4-fold increase in fosfomycin MIC (from 2 to 16 μg/ml) occurred in the fosfomycin-vancomycin group. In summary, the highest eradication of MRSA cage-associated infections was achieved with fosfomycin in combination with rifampin (83%). Fosfomycin may be used in combination with rifampin against MRSA implant-associated infections, but it cannot replace rifampin as an antibiofilm agent.

Olfactory cues potentiate learning of distant visuospatial information

The influence of proximal olfactory cues on place learning and memory was tested in two different spatial tasks. Rats were trained to find a hole leading to their home cage or a single food source in an array of petri dishes. The two apparatuses differed both by the type of reinforcement (return to the home cage or food reward) and the local characteristics of the goal (masked holes or salient dishes). In both cases, the goal was in a fixed location relative to distant visual landmarks and could be marked by a local olfactory cue. Thus, the position of the goal was defined by two sets of redundant cues, each of which was sufficient to allow the discrimination of the goal location. These experiments were conducted with two strains of hooded rats (Long-Evans and PVG), which show different speeds of acquisition in place learning tasks. They revealed that the presence of an olfactory cue marking the goal facilitated learning of its location and that the facilitation persisted after the removal of the cue. Thus, the proximal olfactory cue appeared to potentiate learning and memory of the goal location relative to distant environmental cues. This facilitating effect was only detected when the expression of spatial memory was not already optimal, i.e., during the early phase of acquisition. It was not limited to a particular strain.

Musculoskeletal pain in female asylum seekers and hypovitaminosis D3

Résumé de l'article L'hypovitaminose D3 est bien connue et courante chez la population âgée en Occident. Toutefois, elle est probablement sous-diagnostiquée chez les jeunes femmes immigrantes, bien qu'elle soit bien documentée, principalement en Angleterre dans la population Indo-Pakistanaise. Lorsque ce déficit est diagnostiqué, le traitement substitutif est simple et bon marché. Nous avons suspecté une haute prévalence chez de jeunes femmes requérantes d'asile, surtout chez celles provenant de cultures différant quant à l'exposition solaire et la diète. Nous publions donc une série de 11 cas de patientes avec une hypovitaminose D symptomatique issues de la consultation générale de la Policlinique Médicale Universitaire. Toutes les patientes présentaient une anamnèse d'une faible exposition solaire et de douleurs osseuses diffuses, d'une fatigue, d'une faiblesse musculaire ou des modifications de la marche. Toutefois, les premiers diagnostics évoqués par les médecins étaient une possible somatisation (3 patientes), des douleurs dorso-lombaires chroniques (4 patientes) et des symptômes somatiques multiples et inexpliqués (3 patientes). Le diagnostic a été posé d'emblée chez une patiente seulement. La durée moyenne des plaintes avant la pose du diagnostic était de 38 mois et 5 jours. Avec le traitement de cholecalciférol et de calcium, les symptômes disparaissaient entre 1 et 3 mois, chez une patiente ils ont duré sept mois. Le taux moyen de 250H vitamine D3 était de 10.9 nmol/l (IR 21-131). Le taux moyen de calcium était de 2.19 mmol/l (2.15-2.55) et quatre patientes présentaient une hypocalcémie. Nous pensons donc que les femmes requérantes d'asile sont à risque d'une durée prolongée de symptômes, de part la possible haute prévalence de cette condition et la difficulté chez les médecins à la reconnaître. Le diagnostic d'hypovitaminose devrait être recherché chez les femmes requérantes d'asile souffrant de douleurs musculo-squelettiques de longue durée. Le premier diagnostic souvent évoqué, dans un contexte psychosocial souvent difficile, était de l'ordre d'un trouble somatoforme douloureux ou de somatisations. Toutefois, les douleurs liées à l'hypovitaminose D3 sont relativement bien définies ; elles sont symétriques, osseuses, débutent souvent dans la région lombaire pour ensuite s'étendre au bassin, aux membres inférieures proximalement et à la cage thoracique. Le traitement substitutif est simple, peu onéreux et il serait judicieux d'initier d'autres études pour évaluer le besoin d'une substitution de routine dans la population présentée. Abstract: Deficiency of vitamin D, which can lead to osteomalacia, is common in elderly patients in Western countries. However, it is still widely underdiagnosed in young immigrant women, even though the condition has been extensively reported in the immigrant Indo- Asian population in the United Kingdom since the 1960s. A recent study reports an average 59 months before diagnosis was established, and another study found a prevalence of 78% of hypovitaminosis D3 (compared with 58% in controls) in an Indo-Asian population attending a UK rheumatology clinic. When recognised, hypovitaminosis D3 is easily treatable. A study on osteomalacic myopathy in veiled Arabic women in Denmark found that muscle strength returned to normal (except in maximal voluntary con-traction) after six months' treatment. We expected to see this disease in female asylum seekers, especially in those from societies with different customs regarding exposure to sunlight and diet We report 11 cases of symptomatic hypovitaminosis D3 in female asylum seekers (table 1). We focus on the pathology encountered by the primary care doctors caring for these 11 patients, the length of time between the appearance of symptoms, and the establishment of the diagnosis of hypovitaminosis D3 as well as the women's response to treatment by the improvement of a wide range of clinical symptoms-bone pain, muscular weakness, and fatigue.

Ontogeny and covariation in the Toarcian genus Osperleioceras (Ammonoidea)

Starting from embryonic (protoconch-ammonitella) and early juvenile shells, which are indistinguishable at the species level, growth curves of Osperleioceras from the Reynesi Subzone (Upper Toarcian) of the Causses Basin (Aveyron, France) show a continuous radiating range of correlated variation in dimensional and ornamental characters, such as involution, whorl compression, rib strength and rib density. This covariation pattern can be observed among single-horizon assemblages, as well as during individual ontogenetic development. The existence of a continuous intergradational series of shells, ranging from stout coarsely ribbed to smooth suboxycone morphologies, rules out functional or ecological selectivity to explain this non-random variability pattern. The complex interdependence of shape and sculpture can be simulated by a model in which sculpture intensity depends on mantle curvature [GUEX, 1999]. The expression of covariation in subadult specimens since the base of Upper Toarcian reveals a rise in variability, concomitant with a size decrease, both contemporaneous with environmental instability. It developed in successive bursts from a fairly long low variability period spanning the whole Middle Toarcian.

In vivo survival of teicoplanin-resistant Staphylococcus aureus and fitness cost of teicoplanin resistance.

Glycopeptide resistance, in a set of in vitro step-selected teicoplanin-resistant mutants derived from susceptible Staphylococcus aureus SA113, was associated with slower growth, thickening of the bacterial cell wall, increased N-acetylglucosamine incorporation, and decreased hemolysis. Differential transcriptome analysis showed that as resistance increased, some virulence-associated genes became downregulated. In a mouse tissue cage infection model, an inoculum of 10(4) CFU of strain SA113 rapidly produced a high-bacterial-load infection, which triggered MIP-2 release, leukocyte infiltration, and reduced leukocyte viability. In contrast, with the same inoculum of the isogenic glycopeptide-resistant derivative NM67, CFU initially decreased, resulting in the elimination of the mutant in three out of seven cages. In the four cages in which NM67 survived, it partially regained wild-type characteristics, including thinning of the cell wall, reduced N-acetylglucosamine uptake, and increased hemolysis; however, the survivors also became teicoplanin hypersusceptible. The elimination of the teicoplanin-resistant mutants and selection of teicoplanin-hypersusceptible survivors in the tissue cages indicated that glycopeptide resistance imposes a fitness burden on S. aureus and is selected against in vivo, with restoration of fitness incurring the price of resistance loss.

Measuring alcohol-related consequences in school surveys: alcohol-attributable consequences or consequences with students' alcohol attribution.

In alcohol epidemiology surveys, there is a tradition of measuring alcohol-related consequences using respondents' attribution of alcohol as the cause. The authors aimed to compare the prevalence and frequency of self-attributed consequences to consequences without self-attribution using alcohol-attributable fractions (AAF). In 2007, a total of 7,174 Swiss school students aged 13-16 years reported the numbers of 6 alcohol-related adverse consequences (e.g., fights, injuries) they had incurred in the past 12 months. Consequences were measured with and without attribution of alcohol as the cause. The alcohol-use measures were frequency and volume of drinking in the past 12 months and number of risky single-occasion (> or =5 drinks) drinking episodes in the past 30 days. Attributable fractions were derived from logistic (> or =1 incident) and Poisson (number of incidents) regression analyses. Although relative risk estimates were higher when alcohol-attributed consequences were compared with nonattributed consequences, the use of AAFs resulted in more alcohol-related consequences (10,422 self-attributed consequences vs. 24,520 nonattributed consequences determined by means of AAFs). The likelihood of underreporting was higher among drinkers with intermediate frequencies than among either rare drinkers or frequent drinkers. Therefore, the extent of alcohol-related adverse consequences among adolescents may be underestimated when using self-attributed consequences, because of differential attribution processes, especially among infrequent drinkers.

Choix thérapeutique dans les tumeurs costales primaires [Therapeutic choice in primary costal tumors].

Primary rib tumors constitute a rare entity and have only seldom been studied separately. In a retrospective study based on 21 cases, with the help of the literature, we try to specify the specific problems encountered with rib tumors and the therapeutic consequences that follow. Our series comprises 10 benign tumors, 3 malignant tumors and 8 cartilaginous tumors. The benign tumors were resected and all the patients recovered uneventfully. One of the patients died of a plasmocytoma 92 months after resection. Among the cartilaginous tumors, we observed two recurrences after 9 and 24 months from which the patient died eventually at 20 and 72 months after resection. The histologic diagnosis of a rib tumor must be made through an excisional biopsy. Cartilaginous tumors are potentially malignant. They must be treated as malignant tumors by radical resection and primary reconstruction. The long-term follow-up of every patient carrying a rib tumor is mandatory because of the risk of late recurrence.

Role of rifampin against Propionibacterium acnes biofilm in vitro and in an experimental foreign-body infection model.

Propionibacterium acnes is an important cause of orthopedic-implant-associated infections, for which the optimal treatment has not yet been determined. We investigated the activity of rifampin, alone and in combination, against planktonic and biofilm P. acnes in vitro and in a foreign-body infection model. The MIC and the minimal bactericidal concentration (MBC) were 0.007 and 4 μg/ml for rifampin, 1 and 4 μg/ml for daptomycin, 1 and 8 μg/ml for vancomycin, 1 and 2 μg/ml for levofloxacin, 0.03 and 16 μg/ml for penicillin G, 0.125 and 512 μg/ml for clindamycin, and 0.25 and 32 μg/ml for ceftriaxone. The P. acnes minimal biofilm eradication concentration (MBEC) was 16 μg/ml for rifampin; 32 μg/ml for penicillin G; 64 μg/ml for daptomycin and ceftriaxone; and ≥128 μg/ml for levofloxacin, vancomycin, and clindamycin. In the animal model, implants were infected by injection of 10⁹ CFU P. acnes in cages. Antimicrobial activity on P. acnes was investigated in the cage fluid (planktonic form) and on explanted cages (biofilm form). The cure rates were 4% for daptomycin, 17% for vancomycin, 0% for levofloxacin, and 36% for rifampin. Rifampin cured 63% of the infected cages in combination with daptomycin, 46% with vancomycin, and 25% with levofloxacin. While all tested antimicrobials showed good activity against planktonic P. acnes, for eradication of biofilms, rifampin was needed. In combination with rifampin, daptomycin showed higher cure rates than with vancomycin in this foreign-body infection model.

The influence of drinking pattern, at individual and aggregate levels, on alcohol-related negative consequences.

AIM: To determine the extent drinking patterns (at the individual and country level) are associated with alcohol-related consequences over and above the total alcohol the person consumes. METHODS: Hierarchical linear models were estimated based on general population surveys conducted in 18 countries participating in the GENACIS project. RESULTS: In general, the positive association between drinking pattern scores and alcohol-related consequences was found at both the individual and country levels, independent of volume of drinking. In addition, a significant interaction effect indicated that the more detrimental the country's drinking pattern, the less steep the association between the volume of drinking and its consequences. CONCLUSION: Drinking patterns have an independent impact on consequences over and above the relationship between volume and consequences.