Inflammation and TCR Signal Strength Determine the Breadth of the T Cell Response in a Bim-Dependent Manner.

Generating a diverse T cell memory population through vaccination is a promising strategy to overcome pathogen epitope variability and tolerance to tumor Ags. The effector and memory pool becomes broad in TCR diversity by recruiting high- and low-affinity T cells. We wanted to determine which factors dictate whether a memory T cell pool has a broad versus focused repertoire. We find that inflammation increases the magnitude of low- and high-affinity T cell responses equally well, arguing against a synergistic effect of TCR and inflammatory signals on T cell expansion. We dissect the differential effects of TCR signal strength and inflammation and demonstrate that they control effector T cell survival in a bim-dependent manner. Importantly, bim-dependent cell death is overcome with a high Ag dose in the context of an inflammatory environment. Our data define the framework for the generation of a broad T cell memory pool to inform future vaccine design.

Acute ischemic stroke in children versus young adults.

Objective: The aim of this study was to compare children and young adults with acute ischemic stroke (AIS) in 2 large registries.Methods: We compared clinical characteristics, stroke etiology, workup, and outcome (modified Rankin scale score [mRS] at 3-6 months) in children (1 month-16 years) and young adults (16.1-45 years) with AIS. Data of children were collected prospectively in the nationwide Swiss NeuroPediatric Stroke Registry, young adults in the Bernese stroke database. Outcome (mRS) and stroke severity (pediatric adaptation of the National Institutes of Health stroke scale [PedNIHSS]) in children were calculated retrospectively.Results: From January 2000 to December 2008, 128 children and 199 young adults suffered from an AIS. Children were more likely to be male than young adults (62%/49%, p = 0.023) and less frequently had hypertension (p = 0.001), hypercholesterolemia (p = 0.003), and a family history of stroke (p = 0.048). Stroke severity was similar in children and young adults (median PedNIHSS/NIHSS 5/6; p = 0.102). Stroke etiology (original TOAST classification) was more likely to be "other determined cause" in children than in young adults (51%/29%; p < .001). Cervicocerebral artery dissections were less frequent in children than in young adults (10%/23%; p = 0.005). Outcome at 3 to 6 months did not differ between children and young adults (p = 0.907); 59% of children and 60% of young adults had a favorable outcome (mRS 0-1). Mortality was similar among children and young adults (4%/6%; p = 0.436). In multivariate analysis, low PedNIHSS/NIHSS was the most important predictor of favorable outcome (p < 0.001).Interpretation: Although stroke etiology and risk factors in children and young adults are different, stroke severity and clinical outcome were similar in both groups. ANN NEUROL 2011;70:245-254

Rescue of the mature B cell compartment in BAFF-deficient mice by treatment with recombinant Fc-BAFF.

BAFF deficiency in mice impairs B cell development beyond the transitional stage 1 in the spleen and thus severely reduces the size of follicular and marginal zone B cell compartments. Moreover, humoral immune responses in these mice are dramatically impaired. We now addressed the question whether the decrease in mature B cell numbers and the reduced humoral immune responses in BAFF-deficient mice could be overcome by the injection of recombinant BAFF. We therefore engineered a recombinant protein containing the human IgG1 Fc moiety fused to receptor-binding domain of human BAFF (Fc-BAFF). At 1 week after the second injection of this fusion protein a complete rescue of the marginal zone B cell compartment and a 50% rescue of the follicular B cell compartment was observed. Moreover these mice mounted a T cell-dependent humoral immune response indistinguishable from wild-type mice. By day 14 upon arrest of Fc-BAFF treatment mature B cell numbers in the blood dropped by 50%, indicating that the life span of mature B cells in the absence of BAFF is 14 days or less. Collectively these findings demonstrate that injection of Fc-BAFF in BAFF-deficient mice results in a temporary rescue of a functional mature B cell compartment.

Zinc et diarrhées chez les enfants de moins de cinq ans: les recommandations de l'OMS applicables en Suisse [Zinc and diarrhea in children under 5 years: WHO recommendations implemented in Switzerland].

In Europe, acute diarrhea, particularly caused by rotavirus are frequently the cause of epidemics in nurseries, schools, and even hospitals. Studies in many developing countries show that taking 10 to 20 mg per day of zinc for 10 to 14 days, during and after diarrhea, decreases the severity and reduces the number of episodes of diarrhea occurring within 2 to 3 months following the intake of zinc. However, the few studies conducted in developed countries do not confirm or deny its effectiveness in these countries, thereby limiting the global implementation of WHO recommendations for acute diarrhea. The ongoing study at the HEL (Children hospital - Lausanne) aims to promote this additional therapy in children under 5 years of age, perhaps allowing the helvetic application of the new WHO recommendations.

Meal-induced thermogenesis and obesity: is a fat meal a risk factor for fat gain in children?

Diet composition, in particular fat intake, has been suggested to be a risk factor for obesity in humans. Several mechanisms may contribute to explain the impact of fat intake on fat gain. One factor may be the low thermogenesis induced by a mixed meal rich in fat. In a group of 11 girls (10.1 +/- 0.3 yr), 6 obese (body mass index, 25.6 +/- 0.6 kg/m(2)), and 5 nonobese (body mass index, 19 +/- 1.6 kg/m(2)), we tested the hypothesis that a mixed meal rich in fat can elicit energy saving compared with an isocaloric and isoproteic meal rich in carbohydrate. The postabsorptive resting energy expenditure and the thermic effect of a meal (TEM) after a low fat (LF; 20% fat, 68% carbohydrate, and 12% protein) or an isocaloric (2500 kJ or 600 Cal) and isoproteic high fat (HF; 48% fat, 40% carbohydrate, and 12% protein) meal were measured by indirect calorimetry. Each girl repeated the test with a different, randomly assigned menu (HF or LF) 1 week after the first test. TEM, expressed as a percentage of energy intake was significantly higher after a LF meal than after a HF meal (6.5 +/- 0.7% vs. 4.3 +/- 0.4%; P < 0.01). The postprandial respiratory quotient (RQ) was significantly higher after a LF meal than after a HF meal (0.86 +/- 0.013 vs. 0.83 +/- 0.014; P < 0.001). The HF low carbohydrate meal induced a significantly lower increase in carbohydrate oxidation than the LF meal (20.3 +/- 6.2 vs. 61.3 +/- 7.8 mg/min; P < 0.001). On the contrary, fat oxidation was significantly higher after a HF meal than after a LF meal (-1.3 +/- 2.4 vs. -15.1 +/- 3.6 mg/min; P < 0.01). However, the postprandial fat storage was 8-fold higher after a HF meal than after a LF meal (17.2 +/- 1.7 vs. 1.9 +/- 1.8 g; P < 0.001). These results suggest that a high fat meal is able to induce lower thermogenesis and a higher positive fat balance than an isocaloric and isoproteic low fat meal. Therefore, diet composition per se must be taken into account among the various risk factors that induce obesity in children.

Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo

The mammalian target of rapamycin (mTOR), which exists in two functionally distinct complexes, mTORC1 and mTORC2 plays an important role in tumor growth. Whereas the role of mTORC1 has been well characterized in this process, little is known about the functions of mTORC2 in cancer progression. In this study, we explored the specific role of mTORC2 in colon cancer using a short hairpin RNA expression system to silence the mTORC2-associated protein rictor. We found that downregulation of rictor in HT29 and LS174T colon cancer cells significantly reduced cell proliferation. Knockdown of rictor also resulted in a G1 arrest as observed by cell cycle analysis. We further observed that LS174T cells deficient for rictor failed to form tumors in a nude mice xenograft model. Taken together, these results show that the inhibition of mTORC2 reduces colon cancer cell proliferation in vitro and tumor xenograft formation in vivo. They also suggest that specifically targeting mTORC2 may provide a novel treatment strategy for colorectal cancer.

Is there a place for thoracoscopic debridement in the treatment of empyema in children?

BACKGROUND: Video-assisted thoracoscopic debridement has been shown to be a safe and efficient procedure for empyema in the adult patient. Its place in the management of childhood empyema remains controversial. METHODS: Over an 18-month period, 9 children were operated upon for pleural empyema. All children were initially treated with appropriate antibiotics and chest-tube drainage. Indication for surgery were persistent clinical symptoms and loculation of pleural fluid 5 to 7 days following initial treatment. In case of a duration of the illness of less than 14 days, an initial attempt was made to debride the pleural space by thoracoscopy. RESULTS: Mean duration of the illness prior to surgery was 15 days (range: 10-23 days), and mean duration of preoperative conservative treatment 10 days (range: 5-20 days). In five of the nine patients thoracoscopy was performed. In all patients thoracoscopy failed to provide adequate clearance of the diseased pleural space because of the advanced stage of the disease. The procedure was converted to a formal thoracotomy in four patients, the fifth patient continued to deteriorate and required formal thoracotomy and decortication seven days later. CONCLUSION: This limited experience suggests that, with the current management and indications, video-assisted thoracoscopic surgery adds little benefit to the treatment of childhood empyema.

Predicting Adverse Events in Children with Fever and Chemotherapy-Induced Neutropenia. Results of the Prospective Multicenter SPOG 2003 FN Study

PURPOSE To develop a score predicting the risk of adverse events (AEs) in pediatric patients with cancer who experience fever and neutropenia (FN) and to evaluate its performance. PATIENTS AND METHODS Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of future AEs (ie, serious medical complication, microbiologically defined infection, radiologically confirmed pneumonia) was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. Results An AE was reported in 122 (29%) of 423 FN episodes. In 57 episodes (13%), the first AE was known only after reassessment after 8 to 24 hours of inpatient management. Predicting AE at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The score predicting future AE in 358 episodes without known AE at reassessment used the following four variables: preceding chemotherapy more intensive than acute lymphoblastic leukemia maintenance (weight = 4), hemoglobin > or = 90 g/L (weight = 5), leukocyte count less than 0.3 G/L (weight = 3), and platelet count less than 50 G/L (weight = 3). A score (sum of weights) > or = 9 predicted future AEs. The cross-validated performance of this score exceeded the performance of published risk prediction rules. At an overall sensitivity of 92%, 35% of the episodes were classified as low risk, with a specificity of 45% and a negative predictive value of 93%. CONCLUSION This score, based on four routinely accessible characteristics, accurately identifies pediatric patients with cancer with FN at risk for AEs after reassessment.

Long-term sequelae in children surviving adult respiratory distress syndrome.

Nine children surviving severe adult respiratory distress syndrome were studied 0.9 to 4.2 years after the acute illness. They had received artificial ventilation for a mean of 9.4 days, with an Fio2 greater than 0.5 during a mean time of 34 hours and maximal positive end expiratory pressure levels in the range of 8 to 20 cm H2O. Three children had recurrent respiratory symptoms (moderate exertional dyspnea and cough), and two had evidence of fibrosis on chest radiographs. All patients had abnormal lung function; the most prominent findings were ventilation inequalities, as judged by real-time moment ratio analysis of multibreath nitrogen washout curves (abnormal in eight of nine patients) and hypoxemia (seven of nine). Lung volumes were less abnormal; one patient had restrictive and two had obstructive disease. A significant correlation between intensive care measures (Fio2 greater than 0.5 in hours and peak inspiratory plateau pressure) and lung function abnormalities (moment ratio analysis and hypoxemia) was found. A possibly increased susceptibility of the pediatric age group to the primary insult or respiratory therapy of adult respiratory distress syndrome is suggested.

Intensity modulated radiation therapy or stereotactic fractionated radiotherapy for infratentorial ependymoma in children: a multicentric study.

This study was to evaluate the treatment dosimetry, efficacy and toxicity of intensity modulated radiation therapy (IMRT) and fractionated stereotactic radiotherapy (FSRT) in the management of infratentorial ependymoma. Between 1999 and 2007, seven children (median age, 3.1 years) with infratentorial ependymoma were planned with either IMRT (3 patients) or SFRT (4 patients), the latter after conventional posterior fossa irradiation. Two children underwent gross total resection. Median prescribed dose was 59.4 Gy (range, 55.8-60). The median follow-up for surviving patients was 4.8 years (range, 1.3-8). IMRT (median dose, 59.4 Gy) and FSRT (median dose, 55.8 Gy) achieved similar optimal target coverage. Percentages of maximum doses delivered to the cochleae (59.5 vs 85.0% Gy; P = 0.05) were significantly inferior with IMRT, when compared to FSRT planning. Percentages of maximum doses administered to the pituitary gland (38.2 vs 20.1%; P = 0.05) and optic chiasm (38.1 vs 14.1%; P = 0.001) were, however, significantly higher with IMRT, when compared to FSRT planning. No recurrences were observed at the last follow-up. The estimated 3-year progression-free survival and overall survival were 87.5 and 100%, respectively. No grade >1 acute toxicity was observed. Two patients presented late adverse events (grade 2 hypoacousia) during follow-up, without cognitive impairment. IMRT or FSRT for infratentorial ependymomas is effective and associated with a tolerable toxicity level. Both treatment techniques were able to capitalize their intrinsic conformal ability to deliver high-dose radiation. Larger series of patients treated with these two modalities will be necessary to more fully evaluate these delivery techniques.

Elevated inflammatory markers combined with positive pneumococcal urinary antigen are a good predictor of pneumococcal community-acquired pneumonia in children.

BACKGROUND: Our objective was to evaluate procalcitonin (PCT) and C-reactive protein (CRP) as predictors of a pneumococcal etiology in community-acquired pneumonia (CAP) in hospitalized children. METHODS: Children requiring hospitalization for CAP were prospectively enrolled. The following indices were determined: antibodies against pneumococcal surface proteins (anti-PLY, pneumococcal histidine triad D, pneumococcal histidine triad E, LytB and pneumococcal choline-binding protein A), viral serology, nasopharyngeal cultures and polymerase chain reaction for 13 respiratory viruses, blood pneumococcal polymerase chain reaction, pneumococcal urinary antigen, PCT and CRP. Presumed pneumococcal CAP (P-CAP) was defined as a positive blood culture or polymerase chain reaction for Streptococcus pneumoniae or as a pneumococcal surface protein seroresponse (≥2-fold increase). RESULTS: Seventy-five patients were included from which 37 (49%) met the criteria of P-CAP. Elevated PCT and CRP values were strongly associated with P-CAP with odds ratios of 23 (95% confidence interval: 5-117) for PCT and 19 (95% confidence interval: 5-75) for CRP in multivariate analysis. The sensitivity was 94.4% for PCT (cutoff: 1.5 ng/mL) and 91.9% for CRP (cutoff: 100 mg/L). A value≤0.5 ng/mL of PCT ruled out P-CAP in >90% of cases (negative likelihood ratio: 0.08). Conversely, a PCT value≥1.5 ng/mL associated with a positive pneumococcal urinary antigen had a diagnostic probability for P-CAP of almost 80% (positive likelihood ratio: 4.59). CONCLUSIONS: PCT and CRP are reliable predictors of P-CAP. Low cutoff values of PCT allow identification of children at low risk of P-CAP. The association of elevated PCT or CRP with a positive pneumococcal urinary antigen is a strong predictor of P-CAP.

Mesure de la pression artérielle et dépistage de l'hypertension chez l'enfant. [Blood pressure measurement and screening of hypertension in children].

Children with elevated blood pressure are at risk of being hypertensive in adulthood and of developing complications such as ventricular hypertrophy. Obesity is a cause of hypertension. Because the prevalence of obesity is increasing, some authors argue that the systematic screening for hypertension in children and adolescents is justified for early prevention and treatment. Sex, age and height all influence children's blood pressure. When elevated blood pressure is identified, complementary investigations and treatment might be necessary. However, due to the difficulties of obtaining a valid estimate of blood pressure, to the moderate tracking of blood pressure from childhood to adulthood, and the rarity of hypertension cases in childhood, the usefulness of systematic screening of hypertension during childhood is still controversial. Un enfant dont la pression artérielle est élevée a un risque accru d'être hypertendu à l'âge adulte et de présenter des complications telles que l'hypertrophie ventriculaire gauche. L'augmentation de la prévalence de l'obésité justifierait selon certains auteurs le dépistage systématique de l'hypertension dès le plus jeune âge afin d'instaurer des mesures préventives ou curatives précoces. Les normes de pression dépendent du sexe, de l'âge et de la taille de l'enfant. En cas de pression élevée, des investigations complémentaires, voire un traitement, peuvent être indiqués. Au vu des difficultés pour obtenir une mesure fiable, des incertitudes entachant la valeur pronostique d'une pression artérielle élevée et de la rareté des cas d'hypertension, il n'y a pas de consensus sur l'utilité du dépistage systématique de l'hypertension durant l'enfance.