Appropriateness of colonoscopy in Europe (EPAGE II). Surveillance after polypectomy and after resection of colorectal cancer.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for surveillance after polypectomy and after curative-intent resection of colorectal cancer (CRC), and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews and primary studies regarding the evaluation and management of surveillance colonoscopy after polypectomy and after resection of CRC was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: Most CRCs arise from adenomatous polyps. The characteristics of removed polyps, especially the distinction between low-risk adenomas (1 or 2, small [< 1 cm], tubular, no high-grade dysplasia) vs. high-risk adenomas (large [> or = 1 cm], multiple [> 3], high-grade dysplasia or villous features), have an impact on advanced adenoma recurrence. Most guidelines recommend a 3-year follow-up colonoscopy for high-risk adenomas and a 5-year colonoscopy for low-risk adenomas. Despite the lack of evidence to support or refute any survival benefit for follow-up colonoscopy after curative-intent CRC resection, surveillance colonoscopy is recommended by most guidelines. The timing of the first surveillance colonoscopy differs. The expert panel considered that 56 % of the clinical indications for colonoscopy for surveillance after polypectomy were appropriate. For surveillance after CRC resection, it considered colonoscopy appropriate 1 year after resection. CONCLUSIONS: Colonoscopy is recommended as a first-choice procedure for surveillance after polypectomy by all published guidelines and by the EPAGE II criteria. Despite the limitations of the published studies, colonoscopy is also recommended by most of the guidelines and by EPAGE II criteria for surveillance after curative-intent CRC resection.

Phylogenetic conservatism in plant phenology

Phenological events - defined points in the life cycle of a plant or animal - have been regarded as highly plastic traits, reflecting flexible responses to various environmental cues. The ability of a species to track, via shifts in phenological events, the abiotic environment through time might dictate its vulnerability to future climate change. Understanding the predictors and drivers of phenological change is therefore critical. Here, we evaluated evidence for phylogenetic conservatism - the tendency for closely related species to share similar ecological and biological attributes - in phenological traits across flowering plants. We aggregated published and unpublished data on timing of first flower and first leaf, encompassing 4000 species at 23 sites across the Northern Hemisphere. We reconstructed the phylogeny for the set of included species, first, using the software program Phylomatic, and second, from DNA data. We then quantified phylogenetic conservatism in plant phenology within and across sites. We show that more closely related species tend to flower and leaf at similar times. By contrasting mean flowering times within and across sites, however, we illustrate that it is not the time of year that is conserved, but rather the phenological responses to a common set of abiotic cues. Our findings suggest that species cannot be treated as statistically independent when modelling phenological responses.Synthesis. Closely related species tend to resemble each other in the timing of their life-history events, a likely product of evolutionarily conserved responses to environmental cues. The search for the underlying drivers of phenology must therefore account for species' shared evolutionary histories.

Long-term follow-up of four patients with Langer-Giedion syndrome: clinical course and complications.

Long-term observations of individuals with the so-called Langer-Giedion (LGS) or tricho-rhino-phalangeal type II (TRPS2) are scarce. We report here a on follow-up of four LGS individuals, including one first described by Andres Giedion in 1969, and review the sparse publications on adults with this syndrome which comprises ectodermal dysplasia, multiple cone-shaped epiphyses prior to puberty, multiple cartilaginous exostoses, and mostly mild intellectual impairment. LGS is caused by deletion of the chromosomal segment 8q24.11-q24.13 containing among others the genes EXT1 and TRPS1. Most patients with TRPS2 are only borderline or mildly cognitively delayed, and few are of normal intelligence. Their practical skills are better than their intellectual capability, and, for this reason and because of their low self-esteem, they are often underestimated. Some patients develop seizures at variable age. Osteomas on processes of cervical vertebrae may cause pressure on cervical nerves or dissection of cerebral arteries. Joint stiffness is observed during childhood and changes later to joint laxity causing instability and proneness to trauma. Perthes disease is not rare. Almost all males become bald at or soon after puberty, and some develop (pseudo) gynecomastia. Growth hormone deficiency was found in a few patients, TSH deficiency so far only in one. Puberty and fertility are diminished, and no instance of transmission of the deletion from a non-mosaic parent to a child has been observed so far. Several affected females had vaginal atresia with consequent hydrometrocolpos.

Fission yeast: in shape to divide.

How are cell morphogenesis and cell cycle coordinated? The fission yeast is a rod-shaped unicellular organism widely used to study how a cell self-organizes in space and time. Here, we discuss recent advances in understanding how the cell acquires and maintains its regular rod shape and uses it to control cell division. The cellular body plan is established by microtubules, which mark antipodal growth zones and medial division. In turn, cellular dimensions are defined by the small GTPase Cdc42 and downstream regulators of vesicle trafficking. Yeast cells then repetitively use their simple rod shape to orchestrate the position and timing of cell division.

Spatio-temporal variations in reproductive patterns and population structure of Pasiphaea multidentata (Decapoda: Caridea) in the Blanes canyon and adjacent margin, North-western Mediterranean Sea

The bathyal faunal communities of the NW Mediterranean slopes have been studied consistently in the last two decades, with a special focus on population structure, trophic dynamics and benthopelagic coupling of commercial deep-sea decapod crustaceans and fishes (reviewed in Sardà et al. 2004) and associated species (Cartes and Sardà, 1993; Company and Sardà, 1997, 2000; Cartes et al., 2001; Company et al., 2001, 2003, 2004). One of the major topographic features in the North-western Mediterranean slope is the presence of submarine canyons. Canyons play a major role in funnelling energy and organic matter from the shelf to bathyal and abyssal depths (Puig et al., 2000), but the implications of this enhanced organic supply in the deep-sea benthic communities is still mostly unknown. Trophic supply can follow two major pathways – vertical deposition in the water column (Billett et al., 1983; Baldwin et al., 1998; Lampitt et al., 2001) or down-slope advection on the margins (Puig et al., 2001; Bethoux et al., 2002; Canals et al., 2006) – and can be a limiting factor in the deep-sea, being especially important in the oligotrophic Mediterranean Sea (Sardà et al., 2004). Differences in the quantity, quality and timing of organic matter input to the deep seafloor have been used to explain patterns of biomass and abundance in benthic communities (Levin et al., 1994; Gooday & Turley, 1990; Billett et al., 2001; Galéron et al., 2001; Puig et al., 2001; Gage, 2003) as well as other biological process and in particular the existence of seasonal reproduction (Tyler et al., 1994; Company et al., 2004 (MEPS). Reproduction is a highly energetic process tightly linked to food availability and quality.

Homer1a is a core brain molecular correlate of sleep loss.

Sleep is regulated by a homeostatic process that determines its need and by a circadian process that determines its timing. By using sleep deprivation and transcriptome profiling in inbred mouse strains, we show that genetic background affects susceptibility to sleep loss at the transcriptional level in a tissue-dependent manner. In the brain, Homer1a expression best reflects the response to sleep loss. Time-course gene expression analysis suggests that 2,032 brain transcripts are under circadian control. However, only 391 remain rhythmic when mice are sleep-deprived at four time points around the clock, suggesting that most diurnal changes in gene transcription are, in fact, sleep-wake-dependent. By generating a transgenic mouse line, we show that in Homer1-expressing cells specifically, apart from Homer1a, three other activity-induced genes (Ptgs2, Jph3, and Nptx2) are overexpressed after sleep loss. All four genes play a role in recovery from glutamate-induced neuronal hyperactivity. The consistent activation of Homer1a suggests a role for sleep in intracellular calcium homeostasis for protecting and recovering from the neuronal activation imposed by wakefulness.

Mechanisms of reproductive isolation between an ant species of hybrid origin and one of its parents.

The establishment of new species by hybridization is difficult because it requires the development of reproductive isolation (RI) in sympatry to escape the homogenizing effects of gene flow from the parental species. Here we investigated the role of two pre- and two postzygotic mechanisms of RI in a system comprising two interdependent Pogonomyrmex harvester ant lineages (the H1 and H2 lineages) of hybrid origin and one of their parental species (P. rugosus). Similar to most other ants, P. rugosus is characterized by an environmental system of caste determination with female brood developing either into queens or workers depending on nongenetic factors. By contrast, there is a strong genetic component to caste determination in the H1 and H2 lineages because the developmental fate of female brood depends on the genetic origin of the parents, with interlineage eggs developing into workers and intralineage eggs developing into queens. The study of a mixed mating aggregation revealed strong differences in mating flight timing between P. rugosus and the two lineages as a first mechanism of RI. A second important prezygotic mechanism was assortative mating. Laboratory experiments also provided support for one of the two investigated mechanisms of postzygotic isolation. The majority of offspring produced from the few matings between P. rugosus and the lineages aborted at the egg stage. This hybrid inviability was under maternal influence, with hybrids produced by P. rugosus queens being always inviable whereas a small proportion of H2 lineage queens produced large numbers of adult hybrid offspring. Finally, we found no evidence that genetic caste determination acted as a second postzygotic mechanism reducing gene flow between P. rugosus and the H lineages. The few viable P. rugosus-H hybrids were not preferentially shunted into functionally sterile workers but developed into both workers and queens. Overall, these results reveal that the nearly complete (99.5%) RI between P. rugosus and the two hybrid lineages stems from the combination of two typical prezygotic mechanisms (mating time divergence and assortative mating) and one postzygotic mechanism (hybrid inviability).

Toxic phytoplankton response to warming in two Mediterranean bays of the Ebro Delta

The analysis of the phytoplankton and environmental parameters of the time series in Alfacs and Fangar bays (north western Mediterranean) from 1990 to 2009 shows some trends. There is an increase in the average water column temperature, 0.11, 0.01, 0.80 and 0.23 ºC for spring, summer, fall and winter respectively in Alfacs Bay and 1.76, 0.71, 1.33, 0.89 ºC for spring, summer, fall and winter in Fangar Bay. The trends in phytoplankton populations show a shift in the timing of occurrence of Karlodinium spp. blooms and an increase of the Pseudo-nitzschia spp. abundances. There is a lack of correlation between the average seasonal temperatures and the toxic phytoplankton abundances.

Contribution of NFI-C to TGF-β1 signalling and tissue regeneration

Summary : Platelet Derived Growth Factor (PDGF) and Transforming Growth Factor-ß (TGF-ß) are two crucial growth factors in tissue repair and regeneration. They control migration and proliferation of macrophages and fibroblasts, as well as myofibroblast differentiation and synthesis of the new connective tissue. The transcription factor Nuclear Factor I-C (NFI-C) has been implicated in the TGF-ß pathway and regulation of extracellular matrix proteins in vitro. This suggests a possible implication of NFI-C in tissue repair. In this study, our purpose was to identify the NFI-C target genes in TGF-ß1 pathway activation and define the relationship between these two factors in cutaneous wound healing process. High-throughput genomic analysis in wild-type and NFI-C knock-out embryonic fibroblasts indicated that NFI-C acts as a repressor of the expression of genes which transcriptional activity is enhanced by TGF-ß. Interestingly, we found an over representation of genes involved in connective tissue inflammation and repair. In accordance with the genomic analysis, NFI-C-/- mice showed an improvement of skin healing during the inflammatory stage. Analysis of this new phenotype indicated that the expression of PDGFA and PDGF-Ra genes were increased in the wounds of NFI-C-/- mice resulting in early recruitment of macrophages and fibroblasts in the granulation tissue. In correlation with the stimulation effect of TGF-ß on myofibroblast differentiation we found an increased differentiation of these cells in null mice, providing a rationale for rapid wound closure. Thus, in the absence of NFI-C, both TGF-ß and PDGF pathways may be activated, leading to enhanced healing process. Therefore, the inhibition of NFI-C expression could constitute a suitable therapy for healing improvement. In addition, we identified a delay of hair follicle cycle initiation in NFI-C-/- mice. This prompted us to investigate the role of NFI-C in skin appendage. The transition from a quiescent to a proliferative phase requires a perfect timing of signalling modulation, leading to stem cell activation. As a consequence of cycle initiation delay in null mice, the activation of signalling involved in cell proliferation was also retarded. Interestingly, at the crucial moment of cell fate determination, we identified a decrease of CD34 gene in mutant mice. Since CD34 protein is involved in migration of multipotent cells, we suggest that NFI-C may be involved in stem cell mobilisation required for hair follicle renewal. Further investigations of the role of NFI-C in progenitor cell activation will lead to a better understanding of tissue regeneration and raise the possibility of treating alopecia with NFI-C-targeting treatment. In summary, this study demonstrates new regenerative functions of NFI-C in adult mice, which regulates skin repair and hair follicle renewal. Résumé : PDGF et TGF-ß sont des facteurs important du mécanisme de défense immunitaire. Ils influencent la prolifération et migration des macrophages et des fibroblastes, ainsi que la différenciation des myofibroblastes et la formation du nouveau tissu conjonctif. Le facteur de transcription NFI-C a été impliqué dans la voie de signalisation de TGF-ß et dans 1a régulation de l'expression des protéines de la matrice extracellulaire in vitro. Ces études antérieures laissent supposer que NFI-C serait un facteur important du remodelage tissulaire. Cependant le rôle de NFI-C dans un tissu comme la peau n'a pas encore été étudié. Dans ce travail, le but a été de d'identifier la relation qu'il existe entre I~1FI-C et TGF-ßl à un niveau transcriptionnel et dans le processus de cicatrisation cutanée in vivo. Ainsi, une analyse génétique à grande échelle, a permis d'indiquer que NFI-C agit comme un répresseur sur l'expression des gènes dont l'activité transcriptionnelle est activée par TGF-ß. De plus nous avons identifié un groupe de gènes qui controlent le développement et l'inflammation du tissue conjonctif. En relation avec ce résultat, l'absence de NFI-C dans la peau induit une cicatrisation plus rapide pendant la phase inflammatoire. Durant cette période, nous avons montré que les expressions de PDGFA et PDGFRa seraient plus élevées en absence de NFI-C. En conséquence, l'activation de la voie de PDGF induit une infiltration plus importante des macrophages et fibroblastes dans le tissue granuleux des souris mutantes. De plus, en corrélation avec le rôle de TGF-ßl dans la différenciation des myofibroblasts, nous avons observé une différenciation plus importante de ces cellules chez les animaux knock-out, ce qui peut expliquer une contraction plus rapide de la plaie. De plus, nous avons découvert que NFI-C est impliqué dans l'initiation du cycle folliculaire. La caractérisation de ce nouveau phénotype a montré un ralentissement de la transition telogène-anagène des souris NFI-C-/-. Or, un événement clé de cette transition est la modulation de plusieurs signaux moléculaires aboutissant à' l'activation des cellules souches. En corrélation avec le decalage du cycle, l'activation de ces signaux est également décalée dans les souris NFI-C-/-. Ainsi, au commencement de l'anagène, la prolifération des keratinocytes,NFI-C-/- est retardée et corrèle avec une diminution de l'expression de CD34, une protéine responsable de la détermination du migration des cellules multipotentes. Ainsi, NFI-C semble être impliqué dans la mobilisation des cellules souches qui sont nécessaires au renouvellement folliculaire. En résumé, NFI-C est impliqué dans la régulation des signaux moléculaires nécessaires à la réparation tissulaire et son inhibition pourrait constituer un traitement de la cicatrisation. L'analyse de son rôle dans l'activation des cellules souches permettrait de mieux comprendre le renouvellement tissulaire et, à long terme, d'améliorer les techniques de greffe des cellules souches épithéliales ou consituter une cible pour le traitement de l'alopecie.

Zeitpunkt der Medikamenten-einnahme bei Hypertonie und Angina pectoris. Eine kontrollierte Uberwachungsstudie. [Time of drug intake in hypertension and angina pectoris. A controlled monitoring study]

A prospective cross-over study was performed in a general practice environment to assess and compare compliance data obtained by electronic monitoring on a BID or QD regimen in 113 patients with hypertension or angina pectoris. All patients were on a BID regimen (nifedipine SR) during the first month and switched to QD regimen (amlodipine) for another month. Taking compliance (i.e. the proportion of days with correct dosing) improved in 30% of patients (95% confidence interval 19 to 41%, p < 0.001), when switching from a BID to a QD regimen, but at the same time there was a 15% increase (95% confidence interval 5 to 25%, p < 0.02) in the number of patients with one or more no-dosing days. About 8% of patients had a low compliance rate, irrespective of the dosage regimen. Actual dosage intervals were used to estimate extent and timing of periods with unsatisfactory drug activity for various hypothetical drug durations of action, and it appears that the apparent advantage of QD regimen in terms of compliance is clinically meaningful only, when the duration of activity extents beyond the dosage interval in all patients.

MR spectroscopy of the human brain with enhanced signal intensity at ultrashort echo times on a clinical platform at 3T and 7T.

Recently, the spin-echo full-intensity acquired localized (SPECIAL) spectroscopy technique was proposed to unite the advantages of short TEs on the order of milliseconds (ms) with full sensitivity and applied to in vivo rat brain. In the present study, SPECIAL was adapted and optimized for use on a clinical platform at 3T and 7T by combining interleaved water suppression (WS) and outer volume saturation (OVS), optimized sequence timing, and improved shimming using FASTMAP. High-quality single voxel spectra of human brain were acquired at TEs below or equal to 6 ms on a clinical 3T and 7T system for six volunteers. Narrow linewidths (6.6 +/- 0.6 Hz at 3T and 12.1 +/- 1.0 Hz at 7T for water) and the high signal-to-noise ratio (SNR) of the artifact-free spectra enabled the quantification of a neurochemical profile consisting of 18 metabolites with Cramér-Rao lower bounds (CRLBs) below 20% at both field strengths. The enhanced sensitivity and increased spectral resolution at 7T compared to 3T allowed a two-fold reduction in scan time, an increased precision of quantification for 12 metabolites, and the additional quantification of lactate with CRLB below 20%. Improved sensitivity at 7T was also demonstrated by a 1.7-fold increase in average SNR (= peak height/root mean square [RMS]-of-noise) per unit-time.

Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

IMPORTANCE: New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). OBJECTIVE: To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS: An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. RESULTS: Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. CONCLUSIONS AND RELEVANCE: After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions.

Congenital Myasthenic Syndromes with COLQ mutations: Long term follow-up

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagenlike tail subunit gene (ColQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We report the time course of clinical manifestations in 15 COLQ-mutated patients followed from 1987 to 2010. All patients suffered from a muscle weakness with onset at birth or in childhood. Ocular and bulbar signs were found in 60% of the patients and delayed pupillary light response in 20% of our patients. EMG study demonstrated a decrement on repetitive nerve stimulation and repetitive compound muscle action potential in all patients. Clinical symptoms strongly fluctuated daily, weekly, monthly or even yearly. Severe relapses were characterized by a general motor weakness associated with pain which resolved spontaneously after a few months whereas the relapses with these symptoms and bulbar signs could last up to several years. Genetic analyses identified 16 different mutations including 9 novel ones. There was no genotype-phenotype correlation. Our study confirms the predominance of oculobulbar signs and the frequency of respiratory distress in COLQrelated CMS. At the end of the follow up of 23 years, interesting findings were (i) the spontaneous reversibility of severe relapses, some of them lasting for up to 5 years (ii) the good prognosis of COLQ-related CMS, since at the end of the follow-up 80% of patients were ambulant and 87% of patients had no respiratory trouble (iii) the efficacy of Ephedrine and, to a lesser extend, of 3-4 DAP. The triggering factors of relapses were esterase inhibitors, effort, puberty, pregnancy and delivery highlighting the importance of hormonal factors in CMS. In conclusion, patients diagnosed with unknown congenital myopathy should undergo an electrophysiological study of neuromuscular junction to identify ColQ-related CMS.

Processament de música basat en el seu contingut

Projecte de recerca elaborat a partir d’una estada a la National University of Singapore Singapur, entre juliol i octubre del 2007. Donada l'explosió de la música a l'internet i la ràpida expansió de les col•leccions de música digital, un repte clau en l'àrea de la informació musical és el desenvolupament de sistemes de processament musical eficients i confiables. L'objectiu de la investigació proposada ha estat treballar en diferents aspectes de l'extracció, modelatge i processat del contingut musical. En particular, s’ha treballat en l'extracció, l'anàlisi i la manipulació de descriptors d'àudio de baix nivell, el modelatge de processos musicals, l'estudi i desenvolupament de tècniques d'aprenentatge automàtic per a processar àudio, i la identificació i extracció d'atributs musicals d'alt nivell. S’han revisat i millorat alguns components d'anàlisis d'àudio i revisat components per a l'extracció de descriptors inter-nota i intra-nota en enregistraments monofónics d'àudio. S’ha aplicat treball previ en Tempo a la formalització de diferents tasques musicals. Finalment, s’ha investigat el processat d'alt nivell de música basandonos en el seu contingut. Com exemple d'això, s’ha investigat com músics professionals expressen i comuniquen la seva interpretació del contingut musical i emocional de peces musicals, i hem usat aquesta informació per a identificar automàticament intèrprets. S’han estudiat les desviacions en paràmetres com to, temps, amplitud i timbre a nivell inter-nota i intra-nota.

Breast stem cells and hormonal mechanisms in carcinogenesis

A woman's risk of breast cancer is strongly affected by her reproductive history. The hormonal milieu is also a key determinant of the course of the disease. Combining mouse genetics with tissue recombination techniques, we have established that the female reproductive hormones, estrogens, progesterone, and prolactin, act sequentially on the mammary epithelium to trigger distinct developmental steps. The hormones impinge directly on a subset of luminal mammary epithelial cells that express the respective hormone receptors and act as sensor cells translating and amplifying systemic signals into local stimuli. Local signaling is stage and age specific. During puberty, estrogens promote proliferation using the EGF family member, amphiregulin, as essential paracrine mediator. In adulthood, progesterone, rather than estrogen, is the major inducer of stem cell activation and cell proliferation of the mammary epithelium. Hormonal signaling modulates crucial developmental pathways that impinge on mammary stem cell populations, while Notch signaling, by inhibiting p63, is central to mammary cell fate determination. Cell proliferation occurs in two waves. The first results from direct stimulation of the small fraction of hormone receptor positive cells. It is followed by a second wave of progesterone-induced proliferation involving mostly hormone receptor negative cells, in which RANKL is a key mediator. A model in which repeated activation of paracrine signaling by progesterone with resulting stem cell activation promotes breast carcinogenesis is proposed.