The limits of brain determinacy.

The genes do not control everything that happens in a cell or an organism, because thermally induced molecular movements and conformation changes are beyond genetic control. The importance of uncontrolled events has been argued from the differences between isogenic organisms reared in virtually identical environments, but these might alternatively be attributed to subtle, undetected differences in the environment. The present review focuses on the uncontrolled events themselves in the context of the developing brain. These are considered at cellular and circuit levels because even if cellular physiology was perfectly controlled by the genes (which it is not), the interactions between different cells might still be uncoordinated. A further complication is that the brain contains mechanisms that buffer noise and others that amplify it. The final resultant of the battle between these contrary mechanisms is that developmental stochasticity is sufficiently low to make neurobehavioural defects uncommon, but a chance component of neural development remains. Thus, our brains and behaviour are not entirely determined by a combination of genes-plus-environment.

Water tanks as ecosystems. Local ecosystemic perception for integral management of water tanks in Tamil Nadu, South India

Water tanks offer from many centuries ago solutions in South India for several problems related with water scarcity. They are a traditional water harvesting system wide spread in this territory, allowing a potential decentralized and participatory management of the local population on their own resources. Although water tanks¿ main function is irrigation, they have many other uses, functions and natural resources associated, involving stakeholders in the villages apart from those farmers making use of the irrigation. Water tanks provide a variety of landscapes and biodiversity that creates a valuable heterogeneous territory. The complexity of such an ecosystem should be managed with an integral perspective, considering all the elements involved and their relations, and understanding that water tanks are not just water deposits. This multidisciplinary study tries to demonstrate the idea of water tanks as ecosystems, describing and analyzing deeply and in an unprecedentedly way the functions, uses, natural resources and stakeholders. The research also focuses in the assessment of the ecosystemic perception of the local population of some villages in Tamil Nadu, employing diverse anthropological methodology.

An investment social network beside the Banco de Barcelona, an unusual case?

[cat] L’extensió de les activitats bancàries al segle XIX va ser liderat per alguns grups socials connectats amb el comerç, que van treure profit de la seva experiència i coneixement per estendre la seva influència al voltant del món del crèdit. A la historiografia espanyola, hi ha un conjunt de treballs que s’han centrat en aquesta gent, però en molts pocs casos s’ha fet una classificació que permeti detectar el conjunt de grups econòmics que han liderat el procés de modernització financera de l’Espanya de mitjans del segle XIX. El principal objectiu del treball és l’anàlisi dels grups socials que van formar el Banco de Barcelona entre 1844 i 1854. Aquesta institució va ser important per a la història financera i bancària d’Espanya per ser pionera en la seva activitat creditícia i d’emissió: a més, la seva experiència va servir com a base en la constitució d’un sistema financer modern a Espanya. En una societat com la catalana de mitjans del segle XIX, la confiança era un factor important per explicar la decisió d’invertir. L’aparició de noves companyies i les seves necessitats d’inversió van transformar el comportaments previs. Quin va ser el comportament dels inversors potencials? Va ser el grup que hi havia al voltant del banc el que va ascendir econòmicament en els anys centrals del segle XIX? La resposta és prou clara, els membres del consell d’administració del Banc de Barcelona formaven un grup apart dins dels grups que sorgeixen a l’economia catalana en el seu conjunt.

Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans.

CYP2D6 is involved in the O-demethylation metabolic pathway of venlafaxine in humans. In this study, we investigated whether this isozyme is stereoselective. Plasma samples from seven CYP2D6 extensive metabolizers (EMs) and five CYP2D6 poor metabolizers (PMs), collected during a period without and with coadministration of quinidine, were analysed. Subjects were administered venlafaxine hydrochloride 18.75 mg orally every 12 h for 48 h on two occasions (1 week apart); once alone and once during the concomitant administration of quinidine sulphate every 12 h. Blood and urine samples were collected under steady-state conditions over one dosing interval (12 h). The present results show that, although CYP2D6 catalyses the O-demethylation of both enantiomers of venlafaxine, it displays a marked stereoselectivity towards the (R)-enantiomer. The oral clearance of (R)-venlafaxine was found to be nine-fold higher in EMs compared to PMs [median (range) 173 (29-611) l/h versus 20 (16-24) l/h, P < 0.005], while it was two-fold higher for (S)-venlafaxine [73 (32-130) l/h versus 37 (21-44) l/h, P < 0.05]. In EMs, quinidine decreased (R)- and (S)-venlafaxine oral clearance by 12-fold ( 0.05) and four-fold ( 0.05), respectively. In contrast, quinidine did not have any effects on renal clearance of (R)-venlafaxine [4 (2-10) l/h for venlafaxine alone versus 5 (0.6-7) l/h for venlafaxine + quinidine] and of (S)-venlafaxine [4 (1-7) l/h for venlafaxine alone versus 3 (0.4-6) l/h for venlafaxine + quinidine]. The coadministration of quinidine to EMs resulted in an almost complete inhibition of the partial metabolic clearance of (R)-venlafaxine to O-demethylated metabolites [127 (10-493) l/h down to 1 (0.1-3) l/h, 0.05], while a seven-fold reduction was measured for (S)-venlafaxine [47 (14-94) l/h versus 7 (1-19) l/h, 0.05]. In PMs, coadministration of quinidine did not significantly change oral clearance and partial metabolic clearance of (R)- and (S)-venlafaxine to its various metabolites. In contrast, data obtained on the partial metabolic clearance of (R)- and (S)-venlafaxine to N-demethylated metabolites, a reaction which is mediated by CYP3A4, suggest a lack of stereoselectivity of this enzyme.

Consommation de cannabis : quels sont les risques ?

Abstract - Cannabis: what are the risks ? Cannabinoids from cannabis have a dual use and display often opposite pharmacological properties depending on the circumstances of use and the administered dose. Cannabinoids constitute mainly a recreative or addictive substance, but also a therapeutic drug. They can be either neurotoxic or neuroprotector, carcinogenic or an anti-cancer drug, hyperemetic or antiemetic, pro-inflammatory or anti-inflammatory... Improvement in in-door cultivation techniques and selection of high yield strains have resulted in a steadily increase of THC content. Cannabis is the most frequently prohibited drug used in Switzerland and Western countries. About half of teenagers have already experimented cannabis consumption. About 10% of cannabis users smoke it daily and can be considered as cannabis-dependant. About one third of these cannabis smokers are chronically intoxicated. THC, the main psychoactive drug interacts with the endocannnabinoid system which is made of cellular receptors, endogenous ligands and a complex intra-cellular biosynthetic, degradation and intra-cellular messengers machinery. The endocannabinoid system plays a major role in the fine tuning of the nervous system. It is thought to be important in memory, motor learning, and synaptic plasticity. At psychoactive dose, THC impairs psychomotor and neurocognitive performances. Learning and memory abilities are diminished. The risk to be responsible of a traffic car accident is slightly increased after administration of cannabis alone and strongly increased after combined use of alcohol and cannabis. With the exception of young children, cannabis intake does not lead to potentially fatal intoxication. However, cannabis exposure can act as trigger for cardiovascular accidents in rare vulnerable people. Young or vulnerable people are more at risk to develop a psychosis at adulthood and/or to become cannabis-dependant. Epidemiological studies have shown that the risk to develop a schizophrenia at adulthood is increased for cannabis smokers, especially for those who are early consumers. Likewise for the risk of depression and suicide attempt. Respiratory disease can be worsen after cannabis smoking. Pregnant and breast-feeding mothers should not take cannabis because THC gets into placenta and concentrates in breast milk. The most sensitive time-period to adverse side-effects of cannabis starts from foetus and extends to adolescence. The reason could be that the endocannabinoid system, the main target of THC, plays a major role in the setup of neuronal networks in the immature brain. The concomitant use of other psychoactive drugs such as alcohol, benzodiazepines or cocaine should be avoided because of possible mutual interactions. Furthermore, it has been demonstrated that a cross-sensitisation exists between most addictive drugs at the level of the brain reward system. Chronic use of cannabis leads to tolerance and withdrawals symptoms in case of cannabis intake interruption. Apart from the aforementioned unwanted side effects, cannabis displays useful and original medicinal properties which are currently under scientific evaluation. At the moment the benefit/risk ratio is not yet well assessed. Several minor phytocannabinoids or synthetic cannabinoids devoid of psychoactive properties could find their way in the modern pharmacopoeia (e.g. ajulemic acid). For therapeutic purposes, special cannabis varieties with unique cannabinoids composition (e.g. a high cannabidiol content) are preferred over those which are currently used for recreative smoking. The administration mode also differs in such a way that inhalation of carcinogenic pyrolytic compounds resulting from cannabis smoking is avoided. This can be achieved by inhaling cannabis vapors at low temperature with a vaporizer device. Résumé Les cannabinoïdes contenus dans la plante de cannabis ont un double usage et possèdent des propriétés opposées suivant les circonstances et les doses employées. Les cannabinoïdes, essentiellement drogue récréative ou d'abus pourraient, pour certains d'entre eux, devenir des médicaments. Selon les conditions d'utilisation, ils peuvent être neurotoxiques ou neuroprotecteurs, carcinogènes ou anticancéreux, hyper-émétiques ou antiémétiques, pro-inflammatoires ou anti-inflammatoires... Les techniques de culture sous serre indoor ainsi que la sélection de variétés de cannabis à fort potentiel de production ont conduit à un accroissement notable des taux de THC. Le cannabis est la drogue illégale la plus fréquemment consommée en Suisse et ailleurs dans le monde occidental. Environ la moitié des jeunes ont déjà expérimenté le cannabis. Environ 10 % des consommateurs le fument quotidiennement et en sont devenus dépendants. Un tiers de ces usagers peut être considéré comme chroniquement intoxiqué. Le THC, la principale substance psychoactive du cannabis, interagit avec le "système endocannabinoïde". Ce système est composé de récepteurs cellulaires, de ligands endogènes et d'un dispositif complexe de synthèse, de dégradation, de régulation et de messagers intra-cellulaires. Le système endocannabinoïde joue un rôle clé dans le réglage fin du système nerveux. Les endocannabinoïdes régulent la mémorisation, l'apprentissage moteur et la plasticité des liaisons nerveuses. À dose psychoactive, le THC réduit les performances psychomotrices et neurocognitives. Les facultés d'apprentissage et de mémorisation sont diminuées. Le risque d'être responsable d'un accident de circulation est augmenté après prise de cannabis, et ceci d'autant plus que de l'alcool aura été consommé parallèlement. À l'exception des jeunes enfants, la consommation de cannabis n'entraîne pas de risque potentiel d'intoxication mortelle. Toutefois, le cannabis pourrait agir comme facteur déclenchant d'accident cardiovasculaire chez de rares individus prédisposés. Les individus jeunes, et/ou vulnérables ont un risque significativement plus élevé de développer une psychose à l'âge adulte ou de devenir dépendant au cannabis. Des études épidémiologiques ont montré que le risque de développer une schizophrénie à l'âge adulte était augmenté pour les consommateurs de cannabis et ceci d'autant plus que l'âge de début de consommation était précoce. Il en va de même pour le risque de dépression. Les troubles respiratoires pourraient être exacerbés par la prise de cannabis. Les femmes enceintes et celles qui allaitent ne devraient pas consommer de cannabis car le THC traverse la barrière hémato-placentaire, en outre, il se concentre dans le lait maternel. La période de la vie la plus sensible aux effets néfastes du cannabis correspond à celle allant du foetus à l'adolescent. Le système endocannabinoïde sur lequel agit le THC serait en effet un acteur majeur orchestrant le développement des réseaux neuronaux dans le cerveau immature. La prise concomitante d'autres psychotropes comme l'alcool, les benzodiazépines ou la cocaïne conduit à des renforcements mutuels de leurs effets délétères. De plus, il a été montré l'existence d'une sensibilité croisée pour la majorité des psychotropes qui agissent sur le système de la récompense, le cannabis y compris, ce qui augmente ainsi le risque de pharmacodépendance. La prise régulière de doses élevées de cannabis entraîne l'apparition d'une tolérance et de symptômes de sevrage discrets à l'arrêt de la consommation. À part les effets négatifs mentionnés auparavant, le cannabis possède des propriétés médicales originales qui sont l'objet d'études attentives. Plusieurs cannabinoïdes mineurs naturels ou synthétiques, comme l'acide ajulémique, pourraient trouver un jour une place dans la pharmacopée. En usage thérapeutique, des variétés particulières de cannabis sont préférées, par exemple celles riches en cannabidiol non psychoactif. Le mode d'administration diffère de celui utilisé en mode récréatif. Par exemple, la vaporisation des cannabinoïdes à basse température est préférée à l'inhalation du "joint".

Additional data for nuclear DNA give new insights into the phylogenetic position of Sorex granarius within the Sorex araneus group.

Many species contain genetic lineages that are phylogenetically intermixed with those of other species. In the Sorex araneus group, previous results based on mtDNA and Y chromosome sequence data showed an incongruent position of Sorex granarius within this group. In this study, we explored the relationship between species within the S. araneus group, aiming to resolve the particular position of S. granarius. In this context, we sequenced a total of 2447 base pairs (bp) of X-linked and nuclear genes from 47 individuals of the S. araneus group. The same taxa were also analyzed within a Bayesian framework with nine autosomal microsatellites. These analyses revealed that all markers apart from mtDNA showed similar patterns, suggesting that the problematic position of S. granarius is best explained by an incongruent behavior by mtDNA. Given their close phylogenetic relationship and their close geographic distribution, the most likely explanation for this pattern is past mtDNA introgression from S. araneus race Carlit to S. granarius.

Foster carers influence brood pathogen resistance in ants.

Social organisms face a high risk of epidemics, and respond to this threat by combining efficient individual and collective defences against pathogens. An intriguing and little studied feature of social animals is that individual pathogen resistance may depend not only on genetic or maternal factors, but also on the social environment during development. Here, we used a cross-fostering experiment to investigate whether the pathogen resistance of individual ant workers was shaped by their own colony of origin or by the colony of origin of their carers. The origin of care-giving workers significantly influenced the ability of newly eclosed cross-fostered Formica selysi workers to resist the fungal entomopathogen Beauveria bassiana. In particular, carers that were more resistant to the fungal entomopathogen reared more resistant workers. This effect occurred in the absence of post-infection social interactions, such as trophallaxis and allogrooming. The colony of origin of eggs significantly influenced the survival of the resulting individuals in both control and pathogen treatments. There was no significant effect of the social organization (i.e. whether colonies contain a single or multiple queens) of the colony of origin of either carers or eggs. Our experiment reveals that social interactions during development play a central role in moulding the resistance of emerging workers.

Prevalence, incidence and indications of hypno-sedative treatments in hospitalized patients aged 75 and older

Introduction Sleep impairment is a common problem in older persons and is associated with adverse health and economic consequences. The most prescribed hypnosedatives in Switzerland are benzodiazepines, benzodiazepine-like hypnosedatives and clomethiazole. In the elderly persons, these medications have been associated with decreased cognitive performance, an increased risk of addiction and an increased risk of falls. The main aim of this study was to determine the prevalence, incidence and indications of hypnosedative prescriptions in older in-patients admitted to a Swiss university hospital. Furthermore, we planned to investigate the possible relationship between hypnosedatives' prescription and patients' falls during the hospital stay and we compared the prevalence of hypnosedative drugs' prescribing between geriatric and non-geriatric clinical wards.Materials & Methods This observational study included all patients aged 75 years or older admitted to a Swiss university hospital for 24 h or more. Prescription-related data were recorded every day for 26 consecutive days in the two geriatric wards, and twice, a week apart, in three non-geriatric wards.Results A total of 204 patients (mean age 84.7 ± 0.7 years, 66% women) were included. The prevalence of hypnosedative drugs prescription was 73% and the incidence was 28% on the two geriatric wards. The most common indications for a prescription on geriatric wards was insomnia (51%), followed by continuation of usual treatment (12%). The most frequently prescribed hypnosedative drug was clomethiazole (64% of the patients), followed by lorazepam (11%). We were not able to demonstrate any significant correlation between the number of hypnosedative drugs prescribed and the number of falls during hospital stay. The prevalence of hypnosedative drugs prescriptions was similar between geriatric and non-geriatric wards. The proportion of patients treated by at least one hypnosedative increased between hospital admission (32%) and discharge (45%).Discussions, Conclusion This study reveals a high prevalence of hypnosedative prescription in medical in-patients aged 75 years or older. Main indication was insomnia and the most frequently prescribed hypnosedative molecule was clomethiazole. Prescription incidence was also very high and the proportion of patients being prescribed a hypnosedative increased during hospital stay. Systematic interventions need to be integrated in order to reduce elderly inpatient exposure to treatments that are associated with adverse health outcomes.Conference information: ESCP 40th International Symposium on Clinical Pharmacy. Clinical Pharmacy: Connecting Care and Outcomes Dublin Ireland, 19-21 October 2011

Trichoptera (INSECTA) collected in Mediterranean river basins in the Iberian Peninsula: taxonomic remarks and notes on ecology

As a result of the GUADALMED project, undertaken in Iberian Mediterranean basins, to which were added samples taken by the junior author in the area, we collected numerous caddisfly larvae, pupae and adults. Some larvae were also reared in the lab to obtain adults and allow proper identification. A total of 90 species were identified, which accounts for more than a fourth of the species known in the Iberian Peninsula and Balearic Islands. Here we confirm the presence of doubtful species in the Iberian Peninsula (Glyphotaelius pellucidus) and we expand the distribution range of others (Lype reducta, Micrasema minimum, Limnephilus guadarramicus, Sericostoma pyrenaicum). Moreover, because of the unconformity of morphological larval characteristics with present taxonomical keys (Mesophylax aspersus) or lack of larvae descriptions (Allogamus mortoni, Stenophylax espanioli), here we include some relevant taxonomical aspects that are useful to identify larvae. A brief description of the larva of a possible new species of Hydropsyche (from now on H. gr. instabilis) is also given. Los tricópteros (Insecta) recolectados en las cuencas mediterráneas de la Península Ibérica: notas taxonómicas y requerimientos ecológicos Como resultado de los estudios realizados en el proyecto GUADALMED en las cuencas de los ríos mediterráneos peninsulares y otros muestreos realizados por la primera autora del trabajo se han recolectado numerosas larvas, pupas y adultos de tricópteros. Algunas larvas fueron criadas en el laboratorio para la obtención de adultos y con ello asegurar su identificación. Se han identificado un total de 90 especies que suponen más de una cuarta parte de las especies actualmente conocidas en la Península Ibérica y Baleares. En este trabajo se confirma la presencia, hasta ahora dudosa en la Península Ibérica, de algunas especies (Glyphotaelius pellucidus) y se amplia el área de distribución de otras (Lype reducta, Micrasema minimum, Limnephilus guadarramicus, Sericostoma pyrenaicum). Además, se incluyen algunos aspectos taxonómicos relevantes para la identificación de algunas larvas en futuros estudios, debido a que las claves ya existentes no describen correctamente la larva (Mesophylax aspersus) o porque se trata de larvas sin describir (Allogamus mortoni, Stenophylax espanioli). Se añade también una somera descripción de la larva de una posible nueva especie de Hydropsyche (citada aquí como H. gr. instabilis) y que requiere un estudio más detallado.

MHC class I expression dependent on bacterial infection and parental factors in whitefish embryos (Salmonidae).

Ecological conditions can influence not only the expression of a phenotype, but also the heritability of a trait. As such, heritable variation for a trait needs to be studied across environments. We have investigated how pathogen challenge affects the expression of MHC genes in embryos of the lake whitefish Coregonus palaea. In order to experimentally separate paternal (i.e. genetic) from maternal and environmental effects, and determine whether and how stress affects the heritable variation for MHC expression, embryos were produced in full-factorial in vitro fertilizations, reared singly, and exposed at 208 degree days (late-eyed stage) to either one of two strains of Pseudomonas fluorescens that differ in their virulence characteristics (one increased mortality, while both delayed hatching time). Gene expression was assessed 48 h postinoculation, and virulence effects of the bacterial infection were monitored until hatching. We found no evidence of MHC class II expression at this stage of development. MHC class I expression was markedly down-regulated in reaction to both pseudomonads. While MHC expression could not be linked to embryo survival, the less the gene was expressed, the earlier the embryos hatched within each treatment group, possibly due to trade-offs between immune function and developmental rate or further factors that affect both hatching timing and MHC expression. We found significant additive genetic variance for MHC class I expression in some treatments. That is, changes in pathogen pressures could induce rapid evolution in MHC class I expression. However, we found no additive genetic variance in reaction norms in our study population.

Preliminary report of the first season work of the International Pluridisciplinary Archaeological Expedition to Bactria 2006

The International Pluridisciplinary Archaeological Expedition in Bactria (IPAEB) was created in 2006.The name underlines the international character of the team (which includes Uzbeks, Spanish, French, British and Greek members), the presence of specialists from various fields apart from archaeology and the fame of Bactria1.

A pilot study on subject-based comprehensive steroid profiling: novel biomarkers to detect testosterone misuse in sports.

Context:  Until now, the testosterone/epitestosterone (T/E) ratio is the main marker for detection of testosterone (T) misuse in athletes. As this marker can be influenced by a number of confounding factors, additional steroid profile parameters indicating T misuse can provide substantiating evidence of doping with endogenous steroids. The evaluation of a steroid profile is currently based upon population statistics. Since large inter-individual variations exist, a paradigm shift towards subject-based references is ongoing in doping analysis. Objective:  Proposition of new biomarkers for the detection of testosterone in sports using extensive steroid profiling and an adaptive model based upon Bayesian inference. Subjects:  6 healthy male volunteers were administered with testosterone undecanoate. Population statistics were performed upon steroid profiles from 2014 male Caucasian athletes participating in official sport competition. Design:  An extended search for new biomarkers in a comprehensive steroid profile combined with Bayesian inference techniques as used in the Athlete Biological Passport resulted in a selection of additional biomarkers that may improve detection of testosterone misuse in sports. Results:  Apart from T/E, 4 other steroid ratios (6α-OH-androstenedione/16α-OH-dehydroepiandrostenedione, 4-OH-androstenedione/16α-OH-androstenedione, 7α-OH-testosterone/7β-OH-dehydroepiandrostenedione and dihydrotestosterone/5β-androstane-3α,17β-diol) were identified as sensitive urinary biomarkers for T misuse. These new biomarkers were rated according to relative response, parameter stability, detection time and discriminative power. Conclusion:  Newly selected biomarkers were found suitable for individual referencing within the concept of the Athlete's Biological Passport. The parameters showed improved detection time and discriminative power compared to the T/E ratio. Such biomarkers can support the evidence of doping with small oral doses of testosterone.

Catch-up growth strategies differ between body structures: interactions between age and structure-specific growth in wild nestling Alpine swifts

1. Little is known on the occurrence and magnitude of faster than normal (catch-up) growth in response to periods of undernutrition in the wild, and the extent to which different body structures compensate and over what timescales is poorly understood. 2. We investigated catch-up growth in nestling Alpine Swifts, Apus melba, by comparing nestling growth trajectories in response to a naturally occurring 1-week period of inclement weather and undernutrition with growth of nestlings reared in a good year. 3. In response to undernutrition, nestlings exhibited a hierarchy of tissues preservation and compensation, with body mass being restored quickly after the end of the period of undernutrition, acceleration of skeletal growth occurring later in development, and compensation in wing length occurring mostly due to a prolongation of growth and delayed fledging. 4. The effect of undernutrition and subsequent catch-up growth was age-dependent, with older nestlings being more resilient to undernutrition, and in turn having less need to compensate later in the development. 5. This shows that young in a free-living bird population can compensate in body mass and body size for a naturally occurring period of undernutrition, and that the timing and extent of compensation varies with age and between body structures.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

BACKGROUND: Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. PURPOSE: To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. METHODS: From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. RESULTS: The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. LIMITATIONS: Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. CONCLUSIONS: BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Perforation colique néonatale focale spontanée en dehors de la grande prématurité : rare et potentiellement insidieuse [Focal spontaneous colic perforation in term or near-term neonates: rare and potentially insidious].

Two cases of neonatal focal spontaneous colic perforations are reported. The 1st infant, born at 36 3/7 weeks gestational age, presented on day 3 with crying, abdominal distension, and liquid stools. Clinical examination showed a slightly irritable hypothermic (35.7 °C) infant with a distended abdomen and few bowel sounds. Blood tests were normal apart from an elevated C-reactive protein level (59 mg/l). The abdomen x-ray was erroneously considered normal. The infant's condition remained stable for nearly 3 days. After reviewing the initial x-ray, pneumoperitoneum was suspected and confirmed by a cross-table lateral abdominal x-ray. The infant was started on antibiotics and operated. Macroscopically, the entire gut was normal apart from a focal sigmoid perforation, which was stitched. A transmural colic biopsy revealed focal vascular dilation but was negative for necrotising enterocolitis or Hirschsprung disease. The infant recovered quickly. She is now a healthy, normal 3-year-old. The 2nd infant, born at 38 5/7 weeks gestational age, presented between day 1 and 2 with clinical signs of infection associated with slowly progressive ileus. The chest and abdomen x-ray was mistakenly considered normal. Frank septicemia developed. After reviewing the initial x-ray, pneumoperitoneum was suspected and confirmed by a cross-table lateral abdominal x-ray. The infant was operated. Macroscopically, the small intestine was normal, the ascending and transverse colons were dilated, and the descending and sigmoid colons were narrow. Three cecal perforations were discovered and stitched. An ileostomy and multiple colic biopsies were also performed. The postoperative course was complicated by persistent septic ileus due to descending and sigmoid colon leaks, which led to colic resections with end-to-end anastomosis. Rectal aspiration biopsies were also performed. At 1 month of age, the infant was discharged from the hospital. The ileostomy was closed in two steps at 2 and 5 months of age. A normal sweat test excluded cystic fibrosis. All colic and rectal biopsies revealed nonspecific inflammatory signs and excluded necrotizing enterocolitis and Hirschsprung disease. Nonspecific irregular thinning of muscularis mucosae and muscularis propria were observed in the two resected colic segments. The boy is now a healthy 7-year-old. The incidence of neonatal focal spontaneous colic perforations at term or close to term is unknown but probably very rare. Our department is the neonatal referral center for approximately 14,000 annual births. In the last 10 years (2000-2009), out of 5115 neonatal admissions in our unit, only ten cases have presented a neonatal spontaneous intestinal perforation, seven of ten in very-low-birth-weight infants and three of ten in term or near-term neonates (one with Hirschsprung disease and the two cases reported herein). In the same period, 108 infants suffered from necrotizing enterocolitis, seven of 108 were term infants and 6 out of 7 had a congenital heart disease. The medical literature is poor on the subject of focal spontaneous colic perforations at term; no risk factor is described. The most specific clinical sign seems to be the abdominal distension. The presence of pneumoperitoneum on an abdominal x-ray is the most sensitive paraclinical sign. In case of an intestinal perforation, surgery must be performed quickly. The vital prognosis seems to be good. The objective of this study was to draw pediatricians' attention to focal spontaneous colic perforations in term or close to term newborns. In the cases reported, the diagnostic delays could have been prevented if the entity - with its radiological manifestation - had been well known.