Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.

OBJECTIVE: To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," published in 2004. DESIGN: Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding. METHODS: We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation (1) indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost) or clearly do not. Weak recommendations (2) indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations. RESULTS: Key recommendations, listed by category, include early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7-10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure > or = 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for postoperative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7-9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B), targeting a blood glucose < 150 mg/dL after initial stabilization (2C); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D). Recommendations specific to pediatric severe sepsis include greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); and a recommendation against the use of recombinant activated protein C in children (1B). CONCLUSIONS: There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.

Ecology and neurophysiology of sleep in two wild sloth species

Study Objectives: Interspecific variation in sleep measured in captivity correlates with various physiological and environmental factors, including estimates of predation risk in the wild. However, it remains unclear whether prior comparative studies have been confounded by the captive recording environment. Herein we examine the impact of predation pressure on sleep in sloths living in the wild. Design: Comparison of two closely related sloth species, one exposed to predation and one free from predation. Setting: Panamanian mainland rainforest (predators present) and island mangrove (predators absent). Participants: Mainland (Bradypus variegatus, 5 males and 4 females) and island (Bradypus pygmaeus, 6 males) sloths. Interventions: None. Measurements and Results: EEG and EMG activity were recorded using a miniature data logger. Although both species spent between 9 and 10 hours per day sleeping, the mainland sloths showed a preference for sleeping at night, whereas island sloths showed no preference for sleeping during the day or night. EEG activity during NREM sleep showed lower low-frequency power, and increased spindle and higher frequency power in island sloths when compared to mainland sloths. Conclusions: In sloths sleeping in the wild, predation pressure influenced the timing of sleep, but not the amount of time spent asleep. The preference for sleeping at night in mainland sloths may be a strategy to avoid detection by nocturnal cats. The pronounced differences in the NREM sleep EEG spectrum remain unexplained, but might be related to genetic or environmental factors.

A behavioral study of alpha-1b adrenergic receptor knockout mice: increased reaction to novelty and selectively reduced learning capacities.

Knockout mice lacking the alpha-1b adrenergic receptor were tested in behavioral experiments. Reaction to novelty was first assessed in a simple test in which the time taken by the knockout mice and their littermate controls to enter a second compartment was compared. Then the mice were tested in an open field to which unknown objects were subsequently added. Special novelty was introduced by moving one of the familiar objects to another location in the open field. Spatial behavior and memory were further studied in a homing board test, and in the water maze. The alpha-1b knockout mice showed an enhanced reactivity to new situations. They were faster to enter the new environment, covered longer paths in the open field, and spent more time exploring the new objects. They reacted like controls to modification inducing spatial novelty. In the homing board test, both the knockout mice and the control mice seemed to use a combination of distant visual and proximal olfactory cues, showing place preference only if the two types of cues were redundant. In the water maze the alpha-1b knockout mice were unable to learn the task, which was confirmed in a probe trial without platform. They were perfectly able, however, to escape in a visible platform procedure. These results confirm previous findings showing that the noradrenergic pathway is important for the modulation of behaviors such as reaction to novelty and exploration, and suggest that this is mediated, at least partly, through the alpha-1b adrenergic receptors. The lack of alpha-1b adrenergic receptors in spatial orientation does not seem important in cue-rich tasks but may interfere with orientation in situations providing distant cues only.

Sports practice among adolescents with chronic health conditions.

OBJECTIVES: To compare the level of sports practice between adolescents with chronic health conditions (CHCs) and control peers and to examine the reasons given by adolescents with CHCs for not practicing any sports in comparison with the control group. DESIGN: School survey. SETTING: Postmandatory schools. PARTICIPANTS: A total of 6790 students (3275 females) aged 16 to 20 years, grouped as adolescents with CHCs (355 females, 354 males) and control peers (2920 females, 3161 males). MAIN EXPOSURE: Chronic health condition was defined using a noncategorical approach including adolescents with a chronic disease and/or a physical handicap. MAIN OUTCOME MEASURES: Sports practice, barriers to sports practice among individuals not practicing any sports, and biological, psychological, socioeducative, and physical activity characteristics. RESULTS: Males with CHCs were less likely than control males to practice sports, whereas no significant difference was observed for females. Chronically ill youth were significantly more likely to report having a CHC as a barrier for not practicing sports. However, the most frequently reported barrier was preference for other activities for males with CHCs and lack of time for control males and for females with and without CHCs. CONCLUSIONS: Having a CHC seems to influence sports practice among males but not females. We recommend that practitioners dealing with adolescents remember to take into account sports practice as part of the care of young patients with CHCs.

Fine structural variations of alphabetaTCRs selected by vaccination with natural versus altered self-antigen in melanoma patients.

Immunotherapy of cancer is often performed with altered "analog" peptide Ags optimized for HLA class I binding, resulting in enhanced immunogenicity, but the induced T cell responses require further evaluation. Recently, we demonstrated fine specificity differences and enhanced recognition of naturally presented Ag by T cells after vaccination with natural Melan-A/MART-1 peptide, as compared with analog peptide. In this study, we compared the TCR primary structures of 1489 HLA-A*0201/Melan-A(26-35)-specific CD8 T cells derived from both cohorts of patients. Although a strong preference for TRAV12-2 segment usage was present in nearly all patients, usage of particular TRAJ gene segments and CDR3alpha composition differed slightly after vaccination with natural vs analog peptide. Moreover, TCR beta-chain repertoires were broader after natural than analog peptide vaccination. In all patients, we observed a marked conservation of the CDR3beta amino acid composition with recurrent sequences centered on a glycyl-leucyl/valyl/alanyl-glycyl motif. In contrast to viral-specific TCR repertoires, such "public" motifs were primarily expressed by nondominant T cell clonotypes, which contrasted with "private" CDR3beta signatures frequently found in T cell clonotypes that dominated repertoires of individual patients. Interestingly, no differences in functional avidity were observed between public and private T cell clonotypes. Collectively, our data indicate that T cell repertoires generated against natural or analog Melan-A peptide exhibited slightly distinct but otherwise overlapping and structurally conserved TCR features, suggesting that the differences in binding affinity/avidity of TCRs toward pMHC observed in the two cohorts of patients are caused by subtle structural TCR variations.

Perinatal care at the limit of viability between 22 and 26 completed weeks of gestation in Switzerland.

Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22-26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases. The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infant's and pregnant woman's best interest. Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role. The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable. In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents. In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered. All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infant's clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn. Life support is continued as long as there is reasonable hope for survival and the infant's burden of intensive care is acceptable. If, on the other hand, the health care team and the parents have to recognise that in the light of a very poor prognosis the burden of the currently used therapies has become disproportionate, intensive care measures are no longer justified and other aspects of care (e.g., relief of pain and suffering) are the new priorities (i.e., redirection of care). If a decision is made to withhold or withdraw life-sustaining therapies, the health care team should focus on comfort care for the dying infant and support for the parents.

Glomus intraradices induces changes in root system architecture of rice independently of common symbiosis signaling

? Arbuscular mycorrhizal fungi colonize the roots of most monocotyledons and dicotyledons despite their different root architecture and cell patterning. Among the cereal hosts of arbuscular mycorrhizal fungi, Oryza sativa (rice) possesses a peculiar root system composed of three different types of roots: crown roots; large lateral roots; and fine lateral roots. Characteristic is the constitutive formation of aerenchyma in crown roots and large lateral roots and the absence of cortex from fine lateral roots. Here, we assessed the distribution of colonization by Glomus intraradices within this root system and determined its effect on root system architecture. ? Large lateral roots are preferentially colonized, and fine lateral roots are immune to arbuscular mycorrhizal colonization. Fungal preference for large lateral roots also occurred in sym mutants that block colonization of the root beyond rhizodermal penetration. ? Initiation of large lateral roots is significantly induced by G. intraradices colonization and does not require a functional common symbiosis signaling pathway from which some components are known to be needed for symbiosis-mediated lateral root induction in Medicago truncatula. ? Our results suggest variation of symbiotic properties among the different rice root-types and induction of the preferred tissue by arbuscular mycorrhizal fungi. Furthermore, signaling for arbuscular mycorrhizal-elicited alterations of the root system differs between rice and M. truncatula.

Health care supply, payment system and medical practice : evidence from obstetric practice

ABSTRACTA significant share of deliveries are performed by Cesarian section (C-section) in Europe and in many developed and developing countries. The aims of this thesis are to highlight the non medical, especially economic and financial, incentives that explain the use of C-section, as well as the medical consequences of C-section on women's health, in regard with other factors of ob¬stetrical care quality such as hospital concentration. Those diagnoses enable us to exhibit ways of improvement of obstetrical care quality in France. Our analysis focus on two countries, France and Switzerland. In the first part of the thesis, we show the influence of two non medical factors on the C-section use, namely the hospital payment system on the one hand and the obstetricians behaviour, especially their demand for leisure, on the other hand. With French data on the year 2003, we show firstly that the fee-for-service payment system of private for profit hospitals induces a higher probability of using C-section. Obstetricians play also a preeminent role in the decision to use a C-section, as the probability of a C-section rises with the number of obstetricians. We then focus on a French reform introduced in 2004, to investigate the impact of Prospective Payment System on obstetric practise. We show that the rise of C-section rate between 2003 and 2006 is mainly caused by changes in hospitals and patients features. Obstetricians practises do not vary a lot for patients with the same risk code. In the mean time however, the number of women coded with a high risk rises. This can be caused by improvements in the quality of coding, obstetricians chosing codes that match better the real health state of their patients. Yet, it can also show that obstetricians change their coding practises to justify the use of certain practises, such as C-section, with no regard to the health state of patients. Financial factors are not the only non medical fac¬tors that can influence the resort to C-section. Using Shelton Brown ΠΙ identification strategy, we focus on the potential impact of obstetricians leisure preference on the use of C-section. We use the distributions of days and hours of delivering and the types of C-section - planned or emergency C-sections - to show that the obstetricians demand for leisure has a significant impact on the resort to C-section, but only in emergency situations. The second part of the thesis deals with some ways to improve obstetric care quality. We use on the one hand swiss and french data to study the impact of C-section on the patients' probability of having an obstetric complication and on the other hand the influence of hospital concentration on the quality of obstetric care. We find the same results as former medical studies about the risks entailed by C-section on obstetric complications.These results prove women ought to be better informed of the medical consequences of C-section and that the slowing of C-section use should be a priority of public health policy. We finally focus on another way to improve obstetric care quality, that is hospital lmarket concentration. We investigate the impact of hospital concentration by integrating the Herfindahl-Hirschman index in our model, on health care quality, measured by the HCUP indicator. We find that hospital concentration has a negative impact on obstetric care quality, which undermines today's policy of hospital closings in France.JEL classification: 112; 118Keywords: Hospital; C-section; Payment System; Counterfactual Estimation; Quality of Care.RÉSUMÉUne part importante des accouchements sont réalisés par césarienne en Europe et dans de nom¬breux pays développés ou en développement. Les objectifs de cette thèse sont de mettre en évidence les déterminants non médicaux, notamment économiques et financiers, expliquant le développe¬ment de cette pratique, ainsi que ses conséquences sur la santé des femmes après Γ accouchement, en lien avec d'autres facteurs comme la concentration locale des structures hospitalières. Les résul¬tats exposés dans cette thèse éclairent les perspectives et voies d'amélioration de la qualité des soins en obstétriques.Notre analyse se concentre sur deux pays : la France et la Suisse. Dans la première partie de la thèse, nous mettons en évidence l'influence de deux déterminants non médicaux sur l'emploi de la césarienne : le système de paiement des hôpitaux d'une part, et le comportement des médecins obstétriciens d'autre part. En étudiant des données françaises de 2003, nous montrons d'abord que le financement à l'acte des établissements privés engendre une hausse de la proba¬bilité de pratiquer une césarienne. Le rôle de l'obstrétricien paraît également déterminant dans la décision d'opérer une césarienne, la probabilité d'employer cette technique augmentant avec le nombre d'obstétriciens. Nous nous intéressons ensuite à l'impact de la mise en place en 2004 du système de paiement prospectif sur l'évolution des pratiques obstétricales entre 2003 et 2006 en France. La hausse du taux de recours à la césarienne entre 2004 et 2006 peut ainsi être principa¬lement imputée aux évolutions des caractéristiques des hôpitaux et des patients, les pratiques des obstétriciens, pour un même codage de la situation du patient, variant peu. Dans le même temps cependant, les pratiques de codage des patients parles obstétriciens évoluent fortement, les femmes étant de plus en plus nombreuses à porter des codes correspondant à des situations à risques. Cette évolution peut indiquer que la qualité du codage en 2006 s'est améliorée par rapport à 2004, le codage correspondant de plus en plus à la situation réelle des patientes. H peut aussi indiquer que les pratiques de codage évoluent pour justifier un recours accru à la césarienne, sans lien avec l'état réel des patientes. Les facteurs financiers ne sont pas les seuls facteurs non médicaux à pouvoir expliquer le recours à la césarienne : nous nous intéressons, en suivant la stratégie d'identifica¬tion de Shelton Brown m, à l'impact potentiel de la demande de loisir des médecins obstétriciens sur la pratique de la césarienne. En utilisant la distribution des jours et heures d'accouchement, et en distinguant les césariennes planifiées de celles effectuées en urgence, nous constatons que la demande de loisir des obstétriciens influence significativement le recours à la césarienne, mais uni¬quement pour les interventions d'urgence. La deuxième partie de la thèse est consacrée à l'étude de la qualité des soins en obstétriques. Nous utilisons des données suisses et françaises pour analyser d'une part l'impact de la césarienne sur la survenue de complications obstétricales et d'autre part l'impact de la concentration des soins sur la qualité des soins en obstétrique. Nons confirmons les résultats antérieurs de la littérature médicale sur la dangerosité de la césarienne comme facteur de complications obstétricales. Ces conclusions montrent que les femmes ont besoin d'être informées des conséquences de la césarienne sur leur santé et que le ralentissement de l'augmentation de la pratique de la césarienne devrait être un objectif de la politique publique de santé. Nous nous in¬téressons à un autre facteur d'amélioration des soins en obstrétique, l'organisation des hôpitaux et particulièrement leur concentration. Nous estimons ainsi l'effet de la concentration sur la qualité des soins obstétriques en intégrant l'indice de Herfindahl-Hirschman dans notre modèle, la qualité des soins étant mesurée à l'aide de l'indicateur HCUP. Nous constatons que la concentration des naissances a un impact négatif sur la qualité des soins en obstétrique, résultat qui va dans le sens contraire des politiques de fermeture d'hôpitaux menées actuellement en France. JEL classification : 112 ; 118Mots-clés : Hôpital ; Césarienne ; Système de paiement ; Contrefactuels ; Qualité des soins, sur la qualité des soins en obstétrique.

Les préférences alimentaires sont-elles influencées par l'index de masse corporelle, l'âge, le sexe ou le tabac [Are food preferences affected by body mass index, age, sex or tobacco?].

In recent decades the percentage of energy derived from dietary fat has increased. The aim of this study was to explore the relationship between food taste preferences, BMI, age, gender and smoking habits. A computerized questionnaire using a hedonic scale (range 0 to 8) to quantify the liking for sweet and savoury, lean and fat foods, was filled by 233 adults: 171 normal weight (131 women, 40 men) and 62 overweight subjects (BMI > 25 kg/m2 42 women, 20 men). The majority of the subjects had a general preference for savoury lean food irrespective of their BMI or gender. Similarly, preference for sweet lean food was not influenced by the magnitude of the BMI. In contrast, overweight subjects had a preference for sweet fat food (p = 0.05) as well as for savoury fat food (p < 0.05). At any age or BMI, men preferred sweet fat food (p < 0.01). This was not the case for women. Overweight men over forty preferred savoury fat food, in contrast to overweight women of the same age (p < 0.01). The same difference existed between normal weight smokers and non-smokers. This study demonstrates that fat food preference plays a potential role in the development of obesity.

Colonoscopy is the preferred colorectal cancer screening method in a population-based program.

BACKGROUND AND STUDY AIMS: Various screening methods for colorectal cancer (CRC) are promoted by professional societies; however, few data are available about the factors that determine patient participation in screening, which is crucial to the success of population-based programs. This study aimed (i) to identify factors that determine acceptance of screening and preference of screening method, and (ii) to evaluate procedure success, detection of colorectal neoplasia, and patient satisfaction with screening colonoscopy. PATIENTS AND METHODS: Following a public awareness campaign, the population aged 50 - 80 years was offered CRC screening in the form of annual fecal occult blood tests, flexible sigmoidoscopy, a combination of both, or colonoscopy. RESULTS: 2731 asymptomatic persons (12.0 % of the target population) registered with and were eligible to take part in the screening program. Access to information and a positive attitude to screening were major determinants of participation. Colonoscopy was the method preferred by 74.8 % of participants. Advanced colorectal neoplasia was present in 8.5 %; its prevalence was higher in males and increased with age. Significant complications occurred in 0.5 % of those undergoing colonoscopy and were associated with polypectomy or sedation. Most patients were satisfied with colonoscopy and over 90 % would choose it again for CRC screening. CONCLUSIONS: In this population-based study, only a small proportion of the target population underwent CRC screening despite an extensive information campaign. Colonoscopy was the preferred method and was safe. The determinants of participation in screening and preference of screening method, together with the distribution of colorectal neoplasia in different demographic categories, provide a rationale for improving screening procedures.

Differential species-specific ectoparasitic mite intensities in two intimately coexisting sibling bat species: resource-mediated host attractiveness or parasite specialization?

1. The mechanisms underlying host choice strategies by parasites remain poorly understood. We address two main questions: (i) do parasites prefer vulnerable or well-fed hosts, and (ii) to what extent is a parasite species specialized towards a given host species? 2. To answer these questions, we investigated, both in the field and in the lab, a host-parasite system comprising one ectoparasitic mite (Spinturnix myoti) and its major hosts, two sibling species of bats (Myotis myotis and M blythii), which coexist intimately in colonial nursery roosts. We exploited the close physical associations between host species in colonial roosts as well as naturally occurring annual variation in food abundance to investigate the relationships between parasite intensities and (i) host species and (ii) individual nutritional status. 3. Although horizontal transmission of parasites was facilitated by the intimate aggregation of bats within their colonial clusters, we found significant interspecific differences in degree of infestation throughout the 6 years of the study, with M. myotis always more heavily parasitized than M. blythii. This pattern was replicated in a laboratory experiment in which any species-specific resistance induced by exploitation of different trophic niches in nature was removed. 4. Within both host species, S. myoti showed a clear preference for individuals with higher nutritional status. In years with high resource abundance, both bat hosts harboured more parasites than in low-resource years, although the relative difference in parasite burden across species was maintained. This pattern of host choice was also replicated in the laboratory. When offered a choice, parasites always colonized better-fed individuals. 5. These results show first that host specialization in our study system occurred. Second, immediate parasite choice clearly operated towards the selection of hosts in good nutritional state.

Evaluation of oral versus intravenous dose of vinorelbine to achieve equivalent blood exposures in patients with solid tumours.

Patient's preference is for oral chemotherapy when both oral and i.v. are available, provided that efficacy is equivalent. Reliable switch from oral to i.v. is possible if correspondence between respective doses has been established. Vinorelbine oral was developed as a line extension of VRL i.v. on the basis that similar AUCs result in similar activities. From a first crossover study on 24 patients receiving VRL 25 mg/m2 i.v. and 80 mg/m2 oral data extrapolation concluded on AUCs bioequivalence between Vinorelbine 30 mg/m2 i.v. and 80 mg/m2 oral. A new trial was performed to support this calculation. In a crossover design study on patients (PS 0-1) with advanced solid tumours (44% breast carcinoma), VRL was administered (30 mg/m2 i.v., 80 mg/m2 oral) with a standard meal and 5-HT3 antagonists, at 2 weeks interval. Pharmacokinetics was performed over 168 h and VRL was measured by LC-MS/MS. Statistics included bioequivalence tests. Forty-eight patients were evaluable for PK: median age 58 years (25-71), PS0/PS1: 20/28, M/F: 11/37. Mean AUCs were 1,230 +/- 290 and 1,216 +/- 521 ng/ml for i.v. and oral, respectively. The confidence interval of the AUC ratio (0.83-1.03) was within the required regulatory range (0.8-1.25) and proved the bioequivalence between the two doses. The absolute bioavailability was 37.8 +/- 16.0%, and close to the value from the first study (40%). Patient tolerability was globally comparable between both forms with no significant difference on either haematological or non-haematological toxicities (grade 3-4). This new study, conducted on a larger population, confirmed the reliable dose correspondence previously established between vinorelbine 80 mg/m2 oral and 30 mg/m2 i.v.

DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites.

STAT transcription factors are expressed in many cell types and bind to similar sequences. However, different STAT gene knock-outs show very distinct phenotypes. To determine whether differences between the binding specificities of STAT proteins account for these effects, we compared the sequences bound by STAT1, STAT5A, STAT5B, and STAT6. One sequence set was selected from random oligonucleotides by recombinant STAT1, STAT5A, or STAT6. For another set including many weak binding sites, we quantified the relative affinities to STAT1, STAT5A, STAT5B, and STAT6. We compared the results to the binding sites in natural STAT target genes identified by others. The experiments confirmed the similar specificity of different STAT proteins. Detailed analysis indicated that STAT5A specificity is more similar to that of STAT6 than that of STAT1, as expected from the evolutionary relationships. The preference of STAT6 for sites in which the half-palindromes (TTC) are separated by four nucleotides (N(4)) was confirmed, but analysis of weak binding sites showed that STAT6 binds fairly well to N(3) sites. As previously reported, STAT1 and STAT5 prefer N(3) sites; however, STAT5A, but not STAT1, weakly binds N(4) sites. None of the STATs bound to half-palindromes. There were no specificity differences between STAT5A and STAT5B.

Guidelines for the clinical management of atrial fibrillation: a practical perspective.

Since the management of atrial fibrillation may be difficult in the individual patient, our purpose was to develop simple clinical recommendations to help the general internist manage this common clinical problem. Systematic review of the literature with evaluation of data-related evidence and framing of graded recommendations. Atrial fibrillation affects some 1% of the population in Western countries and is linked to a significant increase in morbidity and mortality. The management of atrial fibrillation requires individualised evaluation of the risks and benefits of therapeutic modalities, relying whenever possible on simple and validated tools. The two main points requiring a decision in clinical management are 1) whether or not to implement thromboembolic prevention therapy, and 2) whether preference should be given to a "rate control" or "rhythm control" strategy. Thromboembolic prophylaxis should be prescribed after individualised risk assessment: for patients at risk, oral anticoagulation with warfarin decreases the rate of embolic complications by 60% and aspirin by 20%, at the expense of an increased incidence of haemorrhagic complications. "Rate control" and "rhythm control" strategies are probably equivalent, and the choice should also be made on an individualised basis. To assist the physician in making his choices for the care of an atrial fibrillation patient we propose specific tables and algorithms, with graded recommendations. On the evidence of data from the literature we propose simple algorithms and tables for the clinical management of atrial fibrillation in the individual patient.

Role of the hypocretin system in cocaine- and alcohol-related behaviors : evidence from hypocretin-deficient mice

RésuméL'addiction aux drogues est une maladie multifactorieile affectant toutes les strates de notre société. Cependant, la vulnérabilité à développer une addiction dépend de facteurs environnementaux, génétiques et psychosociaux. L'addiction aux drogues est décrite comme étant une maladie chronique avec un taux élevé de rechutes. Elle se caractérise par un besoin irrépressible de consommer une drogue et une augmentation progressive de la consommation en dépit des conséquences néfastes. Les mécanismes cérébraux responsables des dépendances aux drogues ne sont que partiellement élucidés, malgré une accumulation croissante d'évidences démontrant des adaptations au niveau moléculaire et cellulaire au sein des systèmes dopaminergique et glutamatergique. L'identification de nouveaux facteurs neurobiologiques responsables de la vulnérabilité aux substances d'abus est cruciale pour le développement de nouveaux traitements thérapeutiques capables d'atténuer et de soulager les symptômes liés à la dépendance aux drogues.Au cours des dernières années, de nombreuses études ont démontré qu'un nouveau circuit cérébral, le système hypocrétinergique, était impliqué dans plusieurs fonctions physiologiques, tel que l'éveil, le métabolisme énergétique, la motivation, le stress et les comportements liés aux phénomènes de récompense. Le système hypocrétinergique est composé d'environ 3000-4000 neurones issus de l'hypothalamus latéral projetant dans tout ie cerveau. Des souris transgéniques pour le gène des hypocrétines ont été générées et leur phénotype correspond à celui des animaux sauvages, excepté le fait qu'elles soient atteintes d'attaques de sommeil similaires à celles observées chez les patients narcoleptiques. H semblerait que les hypocrétines soient requises pour l'acquisition et l'expression de la dépendance aux drogues. Cependant, le mécanisme précis reste encore à être élucidé. Dans ce rapport, nous rendons compte des comportements liés aux phénomènes de récompense liés à l'alcool et à la cocaine chez les souris knock-out (KO), hétérozygotes (HET) et sauvages (WT).Nous avons, dans un premier temps, évalué l'impact d'injections répétées de cocaïne (15 mg/kg, ip) sur la sensibilisation locomotrice et sur le conditionnement place préférence. Nous avons pu observer que les souris WT, HET et KO exprimaient une sensibilisation locomotrice induite par une administration chronique de cocaïne, cependant les souris déficientes en hypocrétines démontraient une sensibilisation retardée et atténuée. Π est intéressant de mentionner que les mâles HET exprimaient une sensibilisation comportementale intermédiaire. Après normalisation des données, toutes les souris exprimaient une amplitude de sensibilisation similaire, excepté les souris mâles KO qui affichaient, le premier jour de traitement, une sensibilisation locomotrice réduite et retardée, reflétant un phénotype hypoactif plutôt qu'une altération de la réponse aux traitements chroniques de cocaïne. Contre toute attente, toutes les souris femelles exprimaient un pattern similaire de sensibilisation locomotrice à la cocaïne. Nous avons ensuite évalué l'effet d'un conditionnement comportemental à un environnement associé à des injections répétées de cocaine (15 mg / kg ip). Toutes les souris, quelque soit leur sexe ou leur génotype, ont manifesté une préférence marquée pour l'environnement apparié à la cocaïne. Après deux semaines d'abstinence à la cocaïne, les mâles et les femelles déficientes en hypocrétines n'exprimaient plus aucune préférence pour le compartiment précédemment associé à la cocaïne. Alors que les souris WT et HET maintenaient leur préférence pour le compartiment associé à la cocaïne. Pour finir, à l'aide d'un nouveau paradigme appelé IntelliCage®, nous avons pu évaluer la consommation de liquide chez les femelles WT, HET et KO. Lorsqu'il n'y avait que de l'eau disponible, nous avons observé que les femelles KO avaient tendance à moins explorer les quatre coins de la cage. Lorsque les souris étaient exposées à quatre types de solutions différentes (eau, ImM quinine ou 0.2% saccharine, alcool 8% et alcool 16%), les souris KO avaient tendance à moins consommer l'eau sucrée et les solutions alcoolisées. Cependant, après normalisation des données, aucune différence significative n'a pu être observée entre les différents génotypes, suggérant que la consommation réduite d'eau sucrée ou d'alcool peut être incombée à l'hypoactivité des souris KO.Ces résultats confirment que le comportement observé chez les souris KO serait dû à des compensations développementales, puisque la sensibilisation locomotrice et le conditionnement comportemental à la cocaïne étaient similaires aux souris HET et WT. En ce qui concerne la consommation de liquide, les souris KO avaient tendance à consommer moins d'eau sucrée et de solutions alcoolisées. Le phénotype hypoactif des souris déficientes en hypocrétine est probablement responsable de leur tendance à moins explorer leur environnement. Il reste encore à déterminer si l'expression de ce phénotype est la conséquence d'un état de vigilance amoindri ou d'une motivation diminuée à la recherche de récompense. Nos résultats suggèrent que les souris déficientes en hypocrétine affichent une motivation certaine à la recherche de récompense lorsqu'elles sont exposées à des environnements où peu d'efforts sont à fournir afin d'obtenir une récompense.AbstractDrug addiction is a multifactorial disorder affecting human beings regardless their education level, their economic status, their origin or even their gender, but the vulnerability to develop addiction depends on environmental, genetic and psychosocial dispositions. Drug addiction is defined as a chronic relapsing disorder characterized by compulsive drug seeking, with loss of control over drug intake and persistent maladaptive decision making in spite of adverse consequences. The brain mechanisms responsible for drug abuse remain partially unknown despite accumulating evidence delineating molecular and cellular adaptations within the glutamatergic and the dopaminergic systems. However, these adaptations do not fully explain the complex brain disease of drug addiction. The identification of other neurobiological factors responsible for the vulnerability to substance abuse is crucial for the development of promising therapeutic treatments able to alleviate signs of drug dependence.For the past few years, growing evidence demonstrated that a recently discovered brain circuit, the hypocretinergic system, is implicated in many physiological functions, including arousal, energy metabolism, motivation, stress and reward-related behaviors. The hypocretin system is composed of a few thousands neurons arising from the lateral hypothalamus and projecting to the entire brain. Hypocretin- deficient mice have been generated, and unexpectedly, their phenotype resembles that of wild type mice excepting sleep attacks strikingly similar to those of human narcolepsy patients. Evidence suggesting that hypocretins are required for the acquisition and the expression of drug addiction has also been reported; however the precise mechanism by which hypocretins modulate drug seeking behaviors remains a matter of debate. Here, we report alcohol and cocaine reward-related behaviors in hypocretin-deficient mice (KO), as well as heterozygous (HET) and wild type (WT) littermates.We first evaluated the impact of repeated cocaine injections (15 mg/kg, ip) on locomotor sensitization and conditioned place preference. We observed that WT, HET and KO mice exhibited behavioral sensitization following repeated cocaine administrations, but hypocretin deficient males displayed a delayed and attenuated response to chronic cocaine administrations. Interestingly, HET males exhibited an intermediate pattern of behavioral sensitization. However, after standardization of the post-injection data versus the period of habituation prior to cocaine injections, all mice displayed similar amplitudes of behavioral sensitization, except a reduced response in KO males on the first day, suggesting that the delayed and reduced cocaine-induced locomotor sensitization may reflect a hypoactive phenotype and probably not an altered response to repeated cocaine administrations. Unexpectedly, all female mice exhibited similar patterns of cocaine-induced behavioral sensitization. We then assessed the behavioral conditioning for an environment repeatedly paired with cocaine injections (15 mg/kg ip). All mice, whatever their gender or genotype, exhibited a robust preference for the environment previously paired with cocaine administrations. Noteworthy, following two weeks of cocaine abstinence, hypocretin-deficient males and females no longer exhibited any preference for the compartment previously paired with cocaine rewards whereas both WT and HET mice continued manifesting a robust preference. We finally assessed drinking behaviors in WT, HET and KO female mice using a novel paradigm, the IntelliCages®. We report here that KO females tended to less explore the four cage comers where water was easily available. When exposed to four different kinds of liquid solutions (water, ImM quinine or saccharine 0.2%, alcohol 8% and alcohol 16%), KO mice tended to less consume the sweet and the alcoholic beverages. However, after data standardization, no significant differences were noticed between genotypes suggesting that the hypoactive phenotype is most likely accountable for the trend regarding the reduced sweet or alcohol intake in KO.Taken together, the present findings confirm that the behavior seen in Hcrt KO mice likely reflects developmental compensations since only a slightly altered cocaine-induced behavioral sensitization and a normal behavioral conditioning with cocaine were observed in these mice compared to HET and WT littermates. With regards to drinking behaviors, KO mice barely displayed any behavioral changes but a trend for reducing sweet and alcoholic beverages. Overall, the most striking observation is the constant hypoactive phenotype seen in the hypocretin-deficient mice that most likely is accountable for their reduced tendency to explore the environment. Whether this hypoactive phenotype is due to a reduced alertness or reduced motivation for reward seeking remains debatable, but our findings suggest that the hypocretin-deficient mice barely display any altered motivation for reward seeking in environments where low efforts are required to access to a reward.