A 10-year experience in paediatric spontaneous cerebral hemorrhage: which children with headache need more than a clinical examination?

INTRODUCTION: When a child is seen in a clinic with a headache, stroke is certainly not the first on the list of differential diagnoses. In western countries, stroke is typically associated with adults and the elderly. Although rare, haemorrhagic strokes are not exceptional in the paediatric population, as their incidence is around 1/100 000/year. Prompt diagnosis is essential, since delayed treatment may lead to disastrous prognosis in these children. MATERIALS AND METHODS: This is a retrospective review of paediatric cases with spontaneous cerebral haemorrhage that presented in two university hospitals in the last ten years. The experience of these primary and tertiary referral centres comprises 22 consecutive cases that are analysed according to aetiology, presenting symptoms, treatment and outcome. RESULTS: 77% of the children diagnosed with haemorrhagic stroke presented with headaches. 41% of them had a sudden onset, while 9% developed headaches over a period of hours to weeks. While 9% presented only with headaches, the majority had either subtle (diplopia, balance problems) or obvious (focal deficits, unilateral weakness and decreased level of consciousness) concomitant neurological signs. 55% had an arteriovenous malformation (AVM), 18% had an aneurysm and 14% had a cavernous malformation. In 14% the aetiology could not be determined. The majority of haemorrhages (82%) were supratentorial, while 18% bled into the posterior fossa. All children underwent an emergency cerebral CT scan followed by specific investigations. The treatment was dependent on the aetiology as well as the mass effect of the haematoma. In 23% an emergent evacuation of the haematoma was performed. Two children (9%) died, and 75% had a favourable clinical outcome. CONCLUSION: Headaches in children are a common problem, and a small minority may reveal an intracranial haemorrhage with poor prognosis if not treated promptly. Although characterisation of headaches is more difficult in a paediatric population, sudden, unusual or intense headaches should lead to imaging work-up. Any neurological finding, even one as subtle as hemianopsia or dysmetria, should alarm the physician and should be followed by emergency imaging investigation. If the cerebral CT reveals a haemorrhage, the child should be referred immediately to a neurosurgical referral centre without further investigation. The outcome is grim for children presenting in coma with fixed, dilated pupils. The long-term result overall for children after spontaneous intracranial haemorrhage is not dismal and depends critically on specialised management.

Problèmes d'échantillonnage lors d'une enquête sur la plombémie d'enfants citadin [Sampling problems in a survey of blood lead levels in city children].

A study on lead pollution was carried out on a sample of ca. 300 city children. This paper presents the errors producing bias in the sample. It is emphasized that, in Switzerland, the difference between the Swiss and the migrant population (the latter being mainly Italian and Spanish) must be taken into account.

Feedback on hypothalamic TRH transcription is dependent on thyroid hormone receptor N terminus.

The beta thyroid hormone receptor (TRbeta), but not TRalpha1, plays a specific role in mediating T(3)-dependent repression of hypothalamic TRH transcription. To investigate the structural basis of isoform specificity, we compared the transcriptional regulation and DNA binding obtained with chimeric and N-terminally deleted TRs. Using in vivo transfection assays to follow hypothalamic TRH transcription in the mouse brain, we found that TRbeta1 and chimeras with the TRbeta1 N terminus did not affect either transcriptional activation or repression from the rat TRH promoter, whereas N-terminally deleted TRbeta1 impaired T(3)-dependent repression. TRalpha1 or chimeras with the TRalpha1 N terminus reduced T(3)-independent transcriptional activation and blocked T(3)-dependent repression of transcription. Full deletion of the TRalpha1 N terminus restored ligand-independent activation of transcription. No TR isoform specificity was seen after transcription from a positive thyroid hormone response element. Gel mobility assays showed that all TRs tested bound specifically to the main negative thyroid hormone response element in the TRH promoter (site 4). Addition of neither steroid receptor coactivator 1 nor nuclear extracts from the hypothalamic paraventricular nuclei revealed any TR isoform specificity in binding to site 4. Thus N-terminal sequences specify TR T(3)-dependent repression of TRH transcription but not DNA recognition, emphasizing as yet unknown neuron-specific contributions to protein-promoter interactions in vivo.

Allergen-induced IgE-dependent gut inflammation in a human PBMC-engrafted murine model of allergy.

BACKGROUND: Humanized murine models comprise a new tool to analyze novel therapeutic strategies for allergic diseases of the intestine.¦OBJECTIVE: In this study we developed a human PBMC-engrafted murine model of allergen-driven gut inflammation and analyzed the underlying immunologic mechanisms.¦METHODS: Nonobese diabetic (NOD)-scid-γc(-/-) mice were injected intraperitoneally with human PBMCs from allergic donors together with the respective allergen or not. Three weeks later, mice were challenged with the allergen orally or rectally, and gut inflammation was monitored with a high-resolution video miniendoscopic system, as well as histologically.¦RESULTS: Using the aeroallergens birch or grass pollen as model allergens and, for some donors, also hazelnut allergen, we show that allergen-specific human IgE in murine sera and allergen-specific proliferation and cytokine production of human CD4(+) T cells recovered from spleens after 3 weeks could only be measured in mice treated with PBMCs plus allergen. Importantly, these mice had the highest endoscopic scores evaluating translucent structure, granularity, fibrin, vascularity, and stool after oral or rectal allergen challenge and a strong histologic inflammation of the colon. Analyzing the underlying mechanisms, we demonstrate that allergen-associated colitis was dependent on IgE, human IgE receptor-expressing effector cells, and the mediators histamine and platelet-activating factor.¦CONCLUSION: These results demonstrate that allergic gut inflammation can be induced in human PBMC-engrafted mice, allowing the investigation of pathophysiologic mechanisms of allergic diseases of the intestine and evaluation of therapeutic interventions.

The human CFTR protein expressed in CHO cells activates aquaporin-3 in a cAMP-dependent pathway: study by digital holographic microscopy.

The transmembrane water movements during cellular processes and their relationship to ionic channel activity remain largely unknown. As an example, in epithelial cells it was proposed that the movement of water could be directly linked to cystic fibrosis transmembrane conductance regulator (CFTR) protein activity through a cAMP-stimulated aqueous pore, or be dependent on aquaporin. Here, we used digital holographic microscopy (DHM) an interferometric technique to quantify in situ the transmembrane water fluxes during the activity of the epithelial chloride channel, CFTR, measured by patch-clamp and iodide efflux techniques. We showed that the water transport measured by DHM is fully inhibited by the selective CFTR blocker CFTRinh172 and is absent in cells lacking CFTR. Of note, in cells expressing the mutated version of CFTR (F508del-CFTR), which mimics the most common genetic alteration encountered in cystic fibrosis, we also show that the water movement is profoundly altered but restored by pharmacological manipulation of F508del-CFTR-defective trafficking. Importantly, whereas activation of this endogenous water channel required a cAMP-dependent stimulation of CFTR, activation of CFTR or F508del-CFTR by two cAMP-independent CFTR activators, genistein and MPB91, failed to trigger water movements. Finally, using a specific small-interfering RNA against the endogenous aquaporin AQP3, the water transport accompanying CFTR activity decreased. We conclude that water fluxes accompanying CFTR activity are linked to AQP3 but not to a cAMP-stimulated aqueous pore in the CFTR protein.

The Commons and anti-commons problems in the tourism economy

Countries specialised in tourism tend to face two problems with contradictory effects: the commons and the anti-commons, which lead to tourism over- and under-production, respectively. This paper develops a two-period model to analyse the joint effects of both problems on a small and remote tourism economy. Congestion and the complementariness between foreign transport and local tourism services are key features in this type of markets. As a result, direct selling and the presence of foreign tour-operators emerge as possible market arrangements with different implications in terms of welfare and public intervention. Four main results are obtained. First, in the direct selling situation the optimal policy depends on the relative importance of the problems. Second, the existence of tour-operators always leads to tourism over-production. Third, the presence of a single tour-operator does not solve the congestion problem. Lastly, the switch from several tour-operators to a single one is welfare reducing.

Some variational problems from image processing

"Vegeu el resum a l'inici del document del fitxer adjunt."

Sex-dependent selection on an autosomal melanic female ornament promotes the evolution of sex ratio bias.

Sex-dependent selection often leads to spectacularly different phenotypes in males and females. In species in which sexual dimorphism is not complete, it is unclear which benefits females and males derive from displaying a trait that is typical of the other sex. In barn owls (Tyto alba), females exhibit on average larger black eumelanic spots than males but members of the two sexes display this trait in the same range of possible values. In a 12-year study, we show that selection exerted on spot size directly or on genetically correlated traits strongly favoured females with large spots and weakly favoured males with small spots. Intense directional selection on females caused an increase in spot diameter in the population over the study period. This increase is due to a change in the autosomal genes underlying the expression of eumelanic spots but not of sex-linked genes. Female-like males produced more daughters than sons, while male-like females produced more sons than daughters when mated to a small-spotted male. These sex ratio biases appear adaptive because sons of male-like females and daughters of female-like males had above-average survival. This demonstrates that selection exerted against individuals displaying a trait that is typical of the other sex promoted the evolution of specific life history strategies that enhance their fitness. This may explain why in many organisms sexual dimorphism is often not complete.

Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T cells.

NKT cells, defined as T cells expressing the NK cell marker NK1.1, are involved in tumor rejection and regulation of autoimmunity via the production of cytokines. We show in this study that two types of NKT cells can be defined on the basis of their reactivity to the monomorphic MHC class I-like molecule CD1d. One type of NKT cell is positively selected by CD1d and expresses a biased TCR repertoire together with a phenotype found on activated T cells. A second type of NKT cell, in contrast, develops in the absence of CD1d, and expresses a diverse TCR repertoire and a phenotype found on naive T cells and NK cells. Importantly, the two types of NKT cells segregate in distinct tissues. Whereas thymus and liver contain primarily CD1d-dependent NKT cells, spleen and bone marrow are enriched in CD1d-independent NKT cells. Collectively, our data suggest that recognition of tissue-specific ligands by the TCR controls localization and activation of NKT cells.

Dose-dependent positive association between cigarette smoking, abdominal obesity and body fat: cross-sectional data from a population-based survey.

ABSTRACT: BACKGROUND: Although smokers tend to have a lower body-mass index than non-smokers, smoking may favour abdominal body fat accumulation. To our knowledge, no population-based studies have assessed the relationship between smoking and body fat composition. We assessed the association between cigarette smoking and waist circumference, body fat, and body-mass index. METHODS: Height, weight, and waist circumference were measured among 6,123 Caucasians (ages 35-75) from a cross-sectional population-based study in Switzerland. Abdominal obesity was defined as waist circumference>=102 cm for men and >=88 cm for women. Body fat (percent total body weight) was measured by electrical bioimpedance. Age- and sex-specific body fat cut-offs were used to define excess body fat. Cigarettes smoked per day were assessed by self-administered questionnaire. Age-adjusted means and odds ratios were calculated using linear and logistic regression. RESULTS: Current smokers (29% of men and 24% of women) had lower mean waist circumference, body fat percentage, and body-mass index compared with non-smokers. Age-adjusted mean waist circumference and body fat increased with cigarettes smoked per day among smokers. The association between cigarettes smoked per day and body-mass index was non-significant. Compared with light smokers, the adjusted odds ratio (OR) for abdominal obesity in men was 1.28 (0.78-2.10) for moderate smokers and 1.94 (1.15-3.27) for heavy smokers (P=0.03 for trend), and 1.07 (0.72-1.58) and 2.15 (1.26-3.64) in female moderate and heavy smokers, respectively (P<0.01 for trend). Compared with light smokers, the OR for excess body fat in men was 1.05 (95% CI: 0.58-1.92) for moderate smokers and 1.15 (0.60-2.20) for heavy smokers (P=0.75 for trend) and 1.34 (0.89-2.00) and 2.11 (1.25-3.57), respectively in women (P=0.07 for trend). CONCLUSION: Among smokers, cigarettes smoked per day were positively associated with central fat accumulation, particularly in women.

IL-2- and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets.

IL-2 plays a pivotal role in regulating the adaptive immune system by controlling the survival and proliferation of regulatory T (Treg) cells, which are required for the maintenance of immune tolerance. Moreover, IL-2 is implicated in the differentiation and homeostasis of effector T-cell subsets, including T(H)1, T(H)2, T(H)17, and memory CD8+ T cells. The IL-2 receptor is composed of 3 distinct subunits, namely the alpha (CD25), beta (CD122), and gamma (gammac) chains. Of crucial importance for the delivery of IL-2 signals to Treg cells is the expression of CD25, which, along with CD122 and gammac, confers high affinity binding to IL-2. Notably, recent findings suggest a novel role for CD25, whereby CD25 molecules on Treg cells and possibly other cells are capable of influencing T-cell homeostasis by means of IL-2 deprivation. This review explores these findings and integrates them into our current understanding of T-cell homeostasis.

The Visual Dysphagia Questionnaire: Piloting a New Tool for Assessing Food Consistency-Dependent Dysphagia in Eosinophilic Esophagitis

Background and Aims: The international EEsAI study group is currently developing the first activity index specific for Eosinophilic Esophagitis (EoE). None of the existing dysphagia questionnaires takes into account the consistency of the ingested food that considerably impacts the symptom presentation. Goal: To develop an EoE-specific questionnaire assessing dysphagia associated with different food consistencies. Methods: Based on patient chart reviews, an expert panel (EEsAI study group) identified internationally standardized food prototypes typically associated with EoE-related dysphagia. Food consistencies were correlated with EoE-related dysphagia, also considering potential food avoidance. This Visual Dysphagia Questionnaire (VDQ) was then tested, as a pilot, in 10 EoE patients. Results: The following 9 food consistency prototypes were identified: water, soft foods (pudding, jelly), grits, toast bread, French fries, dry rice, ground meat, raw fibrous foods (eg. apple, carrot), solid meat. Dysphagia was ranked on a 5-point Likert scale (0=no difficulties, 5=very severe difficulties, food will not pass). Severity of dysphagia in the 10 EoE patients was related to the eosinophil load and presence of esophageal strictures. Conclusions: The VDQ will be the first EoE-specific tool for assessing dysphagia related to internationally defined food consistencies. It performed well in a pilot study and will now be further evaluated in a cohort study including 100 adult and 100 pediatric EoE patients.

The analysis of approximate quickselect and related problems

Approximate Quickselect, a simple modification of the well known Quickselect algorithm for selection, can be used to efficiently find an element with rank k in a given range [i..j], out of n given elements. We study basic cost measures of Approximate Quickselect by computing exact and asymptotic results for the expected number of passes, comparisons and data moves during the execution of this algorithm. The key element appearing in the analysis of Approximate Quickselect is a trivariate recurrence that we solve in full generality. The general solution of the recurrence proves to be very useful, as it allows us to tackle several related problems, besides the analysis that originally motivated us. In particular, we have been able to carry out a precise analysis of the expected number of moves of the ith element when selecting the jth smallest element with standard Quickselect, where we are able to give both exact and asymptotic results. Moreover, we can apply our general results to obtain exact and asymptotic results for several parameters in binary search trees, namely the expected number of common ancestors of the nodes with rank i and j, the expected size of the subtree rooted at the least common ancestor of the nodes with rank i and j, and the expected distance between the nodes of ranks i and j.

Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer.

BACKGROUND: The mutation status of the BRAF and KRAS genes has been proposed as prognostic biomarker in colorectal cancer. Of them, only the BRAF V600E mutation has been validated independently as prognostic for overall survival and survival after relapse, while the prognostic value of KRAS mutation is still unclear. We investigated the prognostic value of BRAF and KRAS mutations in various contexts defined by stratifications of the patient population. METHODS: We retrospectively analyzed a cohort of patients with stage II and III colorectal cancer from the PETACC-3 clinical trial (N = 1,423), by assessing the prognostic value of the BRAF and KRAS mutations in subpopulations defined by all possible combinations of the following clinico-pathological variables: T stage, N stage, tumor site, tumor grade and microsatellite instability status. In each such subpopulation, the prognostic value was assessed by log rank test for three endpoints: overall survival, relapse-free survival, and survival after relapse. The significance level was set to 0.01 for Bonferroni-adjusted p-values, and a second threshold for a trend towards statistical significance was set at 0.05 for unadjusted p-values. The significance of the interactions was tested by Wald test, with significance level of 0.05. RESULTS: In stage II-III colorectal cancer, BRAF mutation was confirmed a marker of poor survival only in subpopulations involving microsatellite stable and left-sided tumors, with higher effects than in the whole population. There was no evidence for prognostic value in microsatellite instable or right-sided tumor groups. We found that BRAF was also prognostic for relapse-free survival in some subpopulations. We found no evidence that KRAS mutations had prognostic value, although a trend was observed in some stratifications. We also show evidence of heterogeneity in survival of patients with BRAF V600E mutation. CONCLUSIONS: The BRAF mutation represents an additional risk factor only in some subpopulations of colorectal cancers, in others having limited prognostic value. However, in the subpopulations where it is prognostic, it represents a marker of much higher risk than previously considered. KRAS mutation status does not seem to represent a strong prognostic variable.