Loss of Cutaneous TSLP-Dependent Immune Responses Skews the Balance of Inflammation from Tumor Protective to Tumor Promoting.

Inflammation can promote or inhibit cancer progression. In this study we have addressed the role of the proinflammatory cytokine thymic stromal lymphopoietin (TSLP) during skin carcinogenesis. Using conditional loss- and gain-of-function mouse models for Notch and Wnt signaling, respectively, we demonstrate that TSLP-mediated inflammation protects against cutaneous carcinogenesis by acting directly on CD4 and CD8 T cells. Genetic ablation of TSLP receptor (TSLPR) perturbs T-cell-mediated protection and results in the accumulation of CD11b(+)Gr1(+) myeloid cells. These promote tumor growth by secreting Wnt ligands and augmenting β-catenin signaling in the neighboring epithelium. Epithelial specific ablation of β-catenin prevents both carcinogenesis and the accumulation of CD11b(+)Gr1(+) myeloid cells, suggesting tumor cells initiate a feed-forward loop that induces protumorigenic inflammation.

Macronutrients and energy balance in obesity.

Energy balance is the difference between metabolizable energy intake and total energy expenditure. Energy intake is difficult to measure accurately; changes in body weight, for example, are not a good measure of the adequacy of energy intake, because fluctuations in body weight are common even if the overall trend is toward weight loss. It is now customary to assess energy requirements indirectly from total energy expenditure. Total energy expenditure consists of basal metabolism, postprandial thermogenesis, and physical activity. Energy expenditure is related to both body weight and body composition. A reduction in total energy expenditure accompanies weight loss, because basal metabolic rate decreases with the loss of lean tissue mass. Similarly, with weight gain, there is an increase in basal metabolic rate, because lean tissue mass grows to support the increase in fat tissue mass. Excess energy intake over energy expenditure causes weight gain and an accompanying increase in total energy expenditure. Following a period of adaptation, total energy expenditure will match energy intake and body weight will stabilize at a higher level. This same relationship holds for weight loss. Respiratory quotient (measured in steady state) is an indication of the proportion of energy expenditure derived from fat and carbohydrate oxidation. Over long periods of time, fat balance is equivalent to energy balance, as an excess of fat intake over fat oxidation causes fat storage.

Regulation of horizontal gene transfer of the catabolic island ICEclc

ICEclc is a mobile genetic element found in two copies on the chromosome of the bacterium Pseudomonas knackmussii B13. ICEclc harbors genes encoding metabolic pathways for the degradation of chlorocatechols (CLC) and 2-aminophenol (2AP). At low frequencies, ICEclc excises from the chromosome, closes into a circular DNA molecule which can transfer to another bacterium via conjugation. Once in the recipient cell, ICEclc can reintegrate into the chromosome by site-specific recombination. This thesis aimed at identifying the regulatory network underlying the decisions for ICEclc horizontal transfer (HGT). The first chapter is an introduction on integrative and conjugative elements (ICEs) more in general, of which ICEclc is one example. In particular I emphasized the current knowledge of regulation and conjugation machineries of the different classes of ICE. In the second chapter, I describe a transcriptional analysis using microarrays and other experiments to understand expression of ICEclc in exponential and stationary phase. By overlaying transcriptomic profiles with Northern hybridizations and RT- PCR data, we established a transcription map for the entire core region of ICEclc, a region assumed to encode the ICE conjugation process. We also demonstrated how transcription of the ICEclc core is maximal in stationary phase, which correlates to expression of reporter genes fused to key ICEclc promoters. In the third chapter, I present a transcriptome analysis of ICEclc in a variety of different host species, in order to explore whether there are species-specific differences. In the fourth chapter, I focus on the role of a curious ICEclc-encoded TetR-type transcriptional repressor. We find that this gene, which we name mfsR, not only controls its own expression but that of a set of genes for a putative multi-drug efflux pump (mfsABC) as well. By using a combination of biochemical and molecular biology techniques, I could show that MfsR specifically binds to operator boxes in two ICEclc promoters (PmfsR and PmfsA), inhibiting the transcription of both the mfsR and mfsABC-orf38184 operons. Although we could not detect a clear phenotype of an mfsABC deletion, we discuss the implications of pump gene reorganizations in ICEclc and close relatives. In the fifth chapter, we find that mfsR not only controls its own expression and that of the mfsABC operon, but is also indirectly controlling ICEclc transfer. Using gene deletions, microarrays, transfer assays and microscopy-based reporter fusions, we demonstrate that mfsR actually controls a small operon of three regulatory genes. The last gene of this mfsR operon, orf17162, encodes a LysR-type activator that when deleted strongly impairs ICEclc transfer. Interestingly, deletion of mfsR leads to transfer competence in almost all cells, thereby overruling the bistability process in the wild-type. In the final sixth chapter, I discuss the relevance of the present thesis and the resulting perspectives for future studies.

Energy balance in elderly patients after surgery for a femoral neck fracture.

To study energy and protein balances in elderly patients after surgery, spontaneous energy and protein intake and resting energy expenditure (REE) were measured in 20 elderly female patients with a femoral neck fracture (mean age 81 +/- 4, SD, range 74-87 years; weight 53 +/- 8, range 42-68 kg) during a 5-6 day period following surgery. REE, measured over 20-40 min by indirect calorimetry using a ventilated canopy, averaged 0.98 +/- 0.15 kcal/min on day 3 and decreased to 0.93 +/- 0.15 kcal/min on day 8-9 postsurgery (p less than 0.02). REE was positively correlated with body weight (r = 0.69, p less than 0.005). Mean REE extrapolated to 24 hr (24-REE) was 1283 +/- 194 kcal/day. Mean daily food energy intake measured over the 5-day follow-up period was 1097 +/- 333 kcal/day and was positively correlated with 24-REE (r = 0.50, p less than 0.05). Daily energy balance was -235 +/- 351 kcal/day on day 3 (p less than 0.01 vs zero) and -13 +/- 392 kcal/day on day 8-9 postsurgery (NS vs zero) with a mean over the study period of -185 +/- 289 kcal/day (p less than 0.01 vs zero). When an extra 100 kcal/day was allowed for the energy cost of physical activity, mean daily energy balance over the 5-day study period was calculated to be -285 +/- 289 kcal/day (p less than 0.01 vs zero). Measurements of total 24-hr urinary nitrogen (N) excretion were obtained in a subgroup of 14 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Negative impact of hypocaloric feeding and energy balance on clinical outcome in ICU patients.

BACKGROUND AND AIMS: Critically ill patients with complicated evolution are frequently hypermetabolic, catabolic, and at risk of underfeeding. The study aimed at assessing the relationship between energy balance and outcome in critically ill patients. METHODS: Prospective observational study conducted in consecutive patients staying > or = 5 days in the surgical ICU of a University hospital. Demographic data, time to feeding, route, energy delivery, and outcome were recorded. Energy balance was calculated as energy delivery minus target. Data in means+/-SD, linear regressions between energy balance and outcome variables. RESULTS: Forty eight patients aged 57+/-16 years were investigated; complete data are available in 669 days. Mechanical ventilation lasted 11+/-8 days, ICU stay 15+/-9 was days, and 30-days mortality was 38%. Time to feeding was 3.1+/-2.2 days. Enteral nutrition was the most frequent route with 433 days. Mean daily energy delivery was 1090+/-930 kcal. Combining enteral and parenteral nutrition achieved highest energy delivery. Cumulated energy balance was between -12,600+/-10,520 kcal, and correlated with complications (P < 0.001), already after 1 week. CONCLUSION: Negative energy balances were correlated with increasing number of complications, particularly infections. Energy debt appears as a promising tool for nutritional follow-up, which should be further tested. Delaying initiation of nutritional support exposes the patients to energy deficits that cannot be compensated later on.

La visite médicale en pratique hospitalière: entre soins et apprentissage [Conducting ward rounds: a balance between care and teaching].

Every day, hospital doctors spend time at conducting ward rounds. Rounds are a core clinical activity during which doctors interact with patients, synthetise a whole set of informations and make many decisions. In addition, rounds can become a crucial teaching moment, when a trainee gets supervised by an attending physician. However, litterature on the topic of rounds is scarce. This paper summarizes the results of the few key studies focusing on ward rounds. The results are presented in four sections, each one being dedicated to one of the round stakeholders: the trainee or resident, the trainer, the patient and the nurse. An emphasis is put on ward rounds involving both a trainee and a trainer, since such rounds always mean striking a balance between care and teaching.

Effect of a pilot gait and balance training program: The importance of fear of falling.

Purpose: To determine the evolution of fear of falling, and its relationship with gait performance after a 10-week gait and balance training program. Population and methods: Participants (N=50) were community-dwelling elderly persons enrolled voluntarily in a 10-week, low intensity, gait and balance training program. At baseline, fear of falling was assessed using a previously validated version of Tinetti's Fall Efficacy Scale (FES, range 0-120, higher score indicating higher confidence), that assesses one's confidence in performing 12 activities of daily life without falling. Gait parameters were measured over a 20m walk at preferred gait speed, using the Physilog system (Aminian K, et al., J Biomechanics, 2002). This system uses 4 kinematics sensors attached to the lower limbs and a data logger carried by the subject. Follow-up data on fear of falling and gait were collected one week after completion of the program. Results: Overall, 43 (86%) of the participants completed the program. Mean age was 78.1 years, 79% were women. At baseline, mean FES score was 98.8 (range 58-120) and mean gait speed was 0.92 m/sec (range 0.43-1.47). At follow-up, participants modestly improved their FES score (98.8±17.0 vs 103.2±16.0, P=.04) and gait speed (0.92±0.27 vs 0.99±0.26 m/sec, P<.01). In secondary analyses stratified by subject's baseline FES, those with lower than average confidence (N=21) improved significantly both FES score (84.4±11.8 vs 94.5±17.9, P<.01) and gait speed (0.79±0.26 vs 0.90±0.28 m/sec, P<.01), while no similar improvement was observed in subjects (N=22) with higher baseline confidence (112.5±6.6 vs 111.5±7.5, P=.56 and 1.03±0.22 vs 1.07±0.21 m/sec, P=.41). After adjustment for age, gender and baseline gait speed, subjects with lower baseline confidence had higher odds than the others to improve their confidence (AdjOR=10.8, 95%CI 1.8- 64.8 P=.01) and gait speed (AdjOR=3.3, 95%CI 0.6-19.7, P=.19) at follow-up. Conclusions: This pilot program of low intensity exercise modestly improved participants' fear of falling and gait speed. Interestingly, subjects with higher baseline fear of falling seemed more likely to benefit. Despite methodological limitations (pre-post comparisons, small sample), these results suggest that measuring fear of falling might be useful to better target subjects most likely to benefit from similar programs.