Nineteen additional unpredicted transcripts from human chromosome 21.

The identification of all human chromosome 21 (HC21) genes is a necessary step in understanding the molecular pathogenesis of trisomy 21 (Down syndrome). The first analysis of the sequence of 21q included 127 previously characterized genes and predicted an additional 98 novel anonymous genes. Recently we evaluated the quality of this annotation by characterizing a set of HC21 open reading frames (C21orfs) identified by mapping spliced expressed sequence tags (ESTs) and predicted genes (PREDs), identified only in silico. This study underscored the limitations of in silico-only gene prediction, as many PREDs were incorrectly predicted. To refine the HC21 annotation, we have developed a reliable algorithm to extract and stringently map sequences that contain bona fide 3' transcript ends to the genome. We then created a specific 21q graphical display allowing an integrated view of the data that incorporates new ESTs as well as features such as CpG islands, repeats, and gene predictions. Using these tools we identified 27 new putative genes. To validate these, we sequenced previously cloned cDNAs and carried out RT-PCR, 5'- and 3'-RACE procedures, and comparative mapping. These approaches substantiated 19 new transcripts, thus increasing the HC21 gene count by 9.5%. These transcripts were likely not previously identified because they are small and encode small proteins. We also identified four transcriptional units that are spliced but contain no obvious open reading frame. The HC21 data presented here further emphasize that current gene prediction algorithms miss a substantial number of transcripts that nevertheless can be identified using a combination of experimental approaches and multiple refined algorithms.

Macrophage migration inhibitory factor: a regulator of innate immunity.

For more than a quarter of a century, macrophage migration inhibitory factor (MIF) has been a mysterious cytokine. In recent years, MIF has assumed an important role as a pivotal regulator of innate immunity. MIF is an integral component of the host antimicrobial alarm system and stress response that promotes the pro-inflammatory functions of immune cells. A rapidly increasing amount of literature indicates that MIF is implicated in the pathogenesis of sepsis, and inflammatory and autoimmune diseases, suggesting that MIF-directed therapies might offer new treatment opportunities for human diseases in the future.

Accreted fragments of the Late Cretaceous Caribbean-Colombian Plateau in Ecuador

The eastern part of the Western Cordillera of Ecuador includes fragments of an Early Cretaceous ( approximate to 123 Ma) oceanic plateau accreted around 85-80 Ma (San Juan unit). West of this unit and in fault contact with it, another oceanic plateau sequence (Guaranda unit) is marked by the occurrence of picrites, ankaramites, basalts, dolerites and shallow level gabbros. A comparable unit is also exposed in northwestern coastal Ecuador (Pedernales unit). Picrites have LREE-depleted patterns, high epsilonNd(i) and very low Pb isotopic ratios, suggesting that they were derived from an extremely depleted source. In contrast, the ankaramites and Mg-rich basalts are LREE-enriched and have radiogenic Pb isotopic compositions similar to the Galapagos HIMU component; their epsilonNd(i) are slightly lower than those of the picrites. Basalts, dolerites and gabbros differ from the picrites and ankaramites by flat rare earth element (REE) patterns and lower epsilonNd; their Pb isotopic compositions are intermediate between those of the picrites and ankaramites. The ankaramites, Mg-rich basalts, and picrites differ from the lavas from the San Juan-Multitud Unit by higher Pb ratios and lower epsilonNd(i). The Ecuadorian and Gorgona 88-86 Ma picrites are geochemically similar. The Ecuadorian ankaramites and Mg-rich basalts share with the 92-86 Ma Mg-rich basalts of the Caribbean-Colombian Oceanic Plateau (CCOP) similar trace element and Nd and Pb isotopic chemistry. This suggests that the Pedernales and Guaranda units belong to the Late Cretaceous CCOR The geochemical diversity of the Guaranda and Pedernales rocks illustrates the heterogeneity of the CCOP plume source and suggests a multi-stage model for the emplacement of these rocks. Stratigraphic and geological relations strongly suggest that the Guaranda unit was accreted in the late Maastrichtian (approximate to 68-65 Ma). (C) 2002 Elsevier Science B.V. All rights reserved.

Late Jurassic oceanic crust and Upper Cretaceous Caribbean plateau picritic basalts exposed in the Duarte igneous complex, Hispaniola

Four distinct rock units have been recognized near El Aguacate, in the Janico-Juncalito-La Vega area of the Duarte complex (Dominican Republic): (1) serpentinites crosscut by numerous diabasic dikes, (2) basalts interbedded with Late Jurassic ribbon cherts, (3) picrites and ankaramites relatively enriched in incompatible trace elements, and (4) amphibolites and gneissic amphibolites chemically similar to Oceanic Plateau Basalts. Similar Ar-Ar ages of late magmatic amphibole from a picrite, and hornblende from an amphibolite (86.1 +/- 1.3 Ma and 86.7 +/- 1.6 Ma, respectively), suggest that the Duarte picrites are contemporaneous with the Deep Sea Drilling Program Leg 15 and Ocean Drilling Program Leg 126 basalts drilled from the Caribbean oceanic plateau. These basalts are associated with sediments containing Late Cretaceous faunas. Sr, Nd, and Pb data show that enriched picrites and amphibolites are isotopically similar to mafic lavas from previously described Caribbean plateau and Galapagos hotspot basalts. Major element, trace element, and lead isotopic features of Late Jurassic basalts and diabases are consistent with those of normal oceanic crust basalt. However, these basalts differ from typical N-MORB because they have lower epsilon Nd ratios that plot within the range of Ocean Island Basalts. These rocks appear to represent remnants of the Caribbean Jurassic oceanic crust formed from an oceanic ridge possibly close to a hotspot. Later, they were tectonically juxtaposed with Late Cretaceous slices of the Caribbean-Colombian plateau.

Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes.

Inter-individual differences in gene expression are likely to account for an important fraction of phenotypic differences, including susceptibility to common disorders. Recent studies have shown extensive variation in gene expression levels in humans and other organisms, and that a fraction of this variation is under genetic control. We investigated the patterns of gene expression variation in a 25 Mb region of human chromosome 21, which has been associated with many Down syndrome (DS) phenotypes. Taqman real-time PCR was used to measure expression variation of 41 genes in lymphoblastoid cells of 40 unrelated individuals. For 25 genes found to be differentially expressed, additional analysis was performed in 10 CEPH families to determine heritabilities and map loci harboring regulatory variation. Seventy-six percent of the differentially expressed genes had significant heritabilities, and genomewide linkage analysis led to the identification of significant eQTLs for nine genes. Most eQTLs were in trans, with the best result (P=7.46 x 10(-8)) obtained for TMEM1 on chromosome 12q24.33. A cis-eQTL identified for CCT8 was validated by performing an association study in 60 individuals from the HapMap project. SNP rs965951 located within CCT8 was found to be significantly associated with its expression levels (P=2.5 x 10(-5)) confirming cis-regulatory variation. The results of our study provide a representative view of expression variation of chromosome 21 genes, identify loci involved in their regulation and suggest that genes, for which expression differences are significantly larger than 1.5-fold in control samples, are unlikely to be involved in DS-phenotypes present in all affected individuals.

Traitement non chirurgical des rectites postactiniques ou radiques chroniques [Non-surgical treatment of acute and late radiation proctitis]

Pelvic external radiotherapy with or without brachytherapy plays an important role in the management of pelvic cancers. Despite recent technical innovations including conformal three-dimensional (3D) external beam radiotherapy and more recently intensity modulated radiotherapy (IMRT), local side effects can occur secondary to normal tissue damage caused by ionising radiation. Morbidity depends on the anatomic position of the rectum within the pelvis and the fast turnover rate of the mucosa, as well as the characteristics of the radiation treatment and patient co-morbidities. Medical management is sometimes complex and merits herein a short review.

Chromosomal gene movements reflect the recent origin and biology of therian sex chromosomes

Mammalian sex chromosomes stem from ancestral autosomes and have substantially differentiated. It was shown that X-linked genes have generated duplicate intronless gene copies (retrogenes) on autosomes due to this differentiation. However, the precise driving forces for this out-of-X gene "movement" and its evolutionary onset are not known. Based on expression analyses of male germ-cell populations, we here substantiate and extend the hypothesis that autosomal retrogenes functionally compensate for the silencing of their X-linked housekeeping parental genes during, but also after, male meiotic sex chromosome inactivation (MSCI). Thus, sexually antagonistic forces have not played a major role for the selective fixation of X-derived gene copies in mammals. Our dating analyses reveal that although retrogenes were produced ever since the common mammalian ancestor, selectively driven retrogene export from the X only started later, on the placental mammal (eutherian) and marsupial (metatherian) lineages, respectively. Together, these observations suggest that chromosome-wide MSCI emerged close to the eutherian-marsupial split approximately 180 million years ago. Given that MSCI probably reflects the spread of the recombination barrier between the X and Y, crucial for their differentiation, our data imply that these chromosomes became more widely differentiated only late in the therian ancestor, well after the divergence of the monotreme lineage. Thus, our study also provides strong independent support for the recent notion that our sex chromosomes emerged, not in the common ancestor of all mammals, but rather in the therian ancestor, and therefore are much younger than previously thought

Experimental lagochilascariosis: histopathological study of inflammatory response to larval migration in the Murine model

The goal of this study was to investigate the pattern of inflammatory response induced by Lagochilascaris minor in murine experimental model. For this purpose 115 mice were given 1000-3000 L. minor infective eggs "per os" and 51 uninfected mice were considered as controls. Four hours post-inoculation (PI), 3rd stage larvae were seen passing through the mucosa of terminal ends of small intestine. Six hours PI larvae were observed as an embolus inside the portal vein and also migrating through the liver parenchyma. During the first 24 h larvae-containing eggs of L. minor were observed in the lumen of intestinal tract. Two days PI larvae were seen migrating through lung parenchyma associated with an initial neutrophilic perivasculitis. From the 13th day of this experimental study, L. minor larvae were found mainly in skeletal muscles, in the center of granulomas. Concentric fibrosis with mixed inflammatory infiltrate involved the larvae after the 47th day PI, persistently. This experimental murine study with L. minor indicated that the 3rd stage larvae penetrated via ileum-cecal mucosa reaching the liver and probably other tissues through the hematogenic via. Throughout its pathway the larvae induced a granulomatous reaction, with abundant polimorphonuclear cells.

Adult consequences of late adolescent alcohol consumption: a systematic review of cohort studies.

Alcohol is responsible for a significant portion of the global burden of disease. There is widespread concern reported in the media and other sources about drinking trends among young people, particularly heavy episodic or “binge” drinking. Prominent among policy responses, in the UK and elsewhere, have been attempts to manage antisocial behaviour related to intoxication in public spaces. Much less attention has been given to the longer term effects of excessive drinking in adolescence on later adult health and well-being. Some studies suggest that individuals “mature out” of late adolescent drinking behaviour, whilst others identify enduring effects on drinking and broader health and social outcomes in adulthood. If adolescent drinking does not cause later difficulties in adulthood then intervention approaches aimed at addressing the acute consequences of alcohol, such as unintentional injuries and anti-social behaviour, may be the most appropriate solution. If causal relationships do exist, however, this approach will not address the cumulative harms produced by alcohol, unless such intervention successfully modifies the long-term relationship with alcohol, which seems unlikely. To address this issue a systematic review of cohort studies was conducted, as this approach provides the strongest observational study design to evaluate evidence for causal inference.This resource was contributed by The National Documentation Centre on Drug Use.

The impact of vascular burden on late-life depression.

Small vessel pathology and microvascular lesions are no longer considered as minor players in the fields of cognitive impairment and mood regulation. Although frequently found in cognitively intact elders, both neuroimaging and neuropathological data revealed the negative impact on cognitive performances of their presence within neocortical association areas, thalamus and basal ganglia. Unlike cognition, the relationship between these lesions and mood dysregulation is still a matter of intense debate. Early studies focusing on the role of macroinfarct location in the occurrence of post-stroke depression (PSD) led to conflicting data. Later on, the concept of vascular depression proposed a deleterious effect of subcortical lacunes and deep white matter demyelination on mood regulation in elders who experienced the first depressive episode. More recently, the chronic accumulation of lacunes in thalamus, basal ganglia and deep white matter has been considered as a strong correlate of PSD. We provide here a critical overview of neuroimaging and neuropathological sets of evidence regarding the affective repercussions of vascular burden in the aging brain and discuss their conceptual and methodological limitations. Based on these observations, we propose that the accumulation of small vascular and microvascular lesions constitutes a common neuropathological platform for both cognitive decline and depressive episodes in old age.

Asthme a début tardif [Late-onset asthma].

Late-onset asthma is a common disease, with characteristics that differentiate it from childhood asthma persisting in adults, including a heterogeneity of underlying mechanism, a correlation with occupational exposure and the tendency to chronicize. Inadequate perception of the disease importance and difficulties in diagnosis, due to the association to COPD, the broad differential diagnosis spectrum and an atypical clinical manifestation, make this disease entity underdiagnosed and under-treated, with consequences for morbidity and mortality. The treatment of adults with asthma follows the usual guidelines, but must take into account an occasional poor therapeutic response and the risk of side effects in polymorbid patients.

Neutrophil transepithelial migration: role of toll-like receptors in mucosal inflammation

The symptomatic phases of many inflammatory diseases are characterized by migration of large numbers of neutrophils (PMN) across a polarized epithelium and accumulation within a lumen. For example, acute PMN influx is common in diseases of the gastrointestinal system (ulcerative colitis, Crohn's disease, bacterial enterocolitis, gastritis), hepatobiliary system (cholangitis, acute cholecystitis), respiratory tract (bronchial pneumonia, bronchitis, cystic fibrosis, bronchiectasis), and urinary tract (pyelonephritis, cystitis). Despite these observations, the molecular basis of leukocyte interactions with epithelial cells is incompletely understood. In vitro models of PMN transepithelial migration typically use N-formylated bacterial peptides such as fMLP in isolation to drive human PMNs across epithelial monolayers. However, other microbial products such as lipopolysaccharide (LPS) are major constituents of the intestinal lumen and have potent effects on the immune system. In the absence of LPS, we have shown that transepithelial migration requires sequential adhesive interactions between the PMN beta2 integrin CD11b/CD18 and JAM protein family members. Other epithelial ligands appear to be abundantly represented as fucosylated proteoglycans. Further studies indicate that the rate of PMN migration across mucosal surfaces can be regulated by the ubiquitously expressed transmembrane protein CD47 and microbial-derived factors, although many of the details remain unclear. Current data suggests that Toll-like receptors (TLR), which recognize specific pathogen-associated molecular patterns (PAMPs), are differentially expressed on both leukocytes and mucosal epithelial cells while serving to modulate leukocyte-epithelial interactions. Exposure of epithelial TLRs to microbial ligands has been shown to result in transcriptional upregulation of inflammatory mediators whereas ligation of leukocyte TLRs modulate specific antimicrobial responses. A better understanding of these events will hopefully provide new insights into the mechanisms of epithelial responses to microorganisms and ideas for therapies aimed at inhibiting the deleterious consequences of mucosal inflammation.

Failure of neutrophil migration toward infectious focus in severe sepsis: a critical event for the outcome of this syndrome

Sepsis is a systemic inflammatory response commonly caused by bacterial infection. We demonstrated that the outcome of sepsis induced by cecal ligation and puncture (CLP) correlates with the severity of the neutrophil migration failure towards infectious focus. Failure appears to be due to a decrease in the rolling and adhesion of neutrophil to endothelium cells. It seems that neutrophil migration impairment is mediated by the circulating inflammatory cytokines, such as TNF-alpha and IL-8, which induce the nitric oxide (NO) production systemically. It is supported by the fact that intravenous administration of these cytokines reduces the neutrophil migration induced by different inflammatory stimuli, and in severe sepsis the circulating concentrations of the cytokines and chemokines are significantly increased. Moreover, the neutrophil migration failure and the reduction in the rolling/adhesion were not observed in iNOS-/- mice and, aminoguanidine prevented this event. We also demonstrated that the failure of neutrophil migration is a Toll-4 receptor (TLR4) dependent mechanism, since it was not observed in TLR4 deficient mice. Furthermore, it was also observed that circulating neutrophils obtained from septic patients present failure of neutrophil chemotaxis toward fMLP, IL-8, and LTB4 and an increased in sera concentrations of NO3 and cytokines. In conclusion, we demonstrated that, in sepsis, failure of neutrophil migration is critical for the outcome and that NO is involved in the process.

A bacterial artificial chromosome library for Biomphalaria glabrata, intermediate snail host of Schistosoma mansoni

To provide a novel resource for analysis of the genome of Biomphalaria glabrata, members of the international Biomphalaria glabrata Genome Initiative (biology.unm.edu/biomphalaria-genome.html), working with the Arizona Genomics Institute (AGI) and supported by the National Human Genome Research Institute (NHGRI), produced a high quality bacterial artificial chromosome (BAC) library. The BB02 strain B. glabrata, a field isolate (Belo Horizonte, Minas Gerais, Brasil) that is susceptible to several strains of Schistosoma mansoni, was selfed for two generations to reduce haplotype diversity in the offspring. High molecular weight DNA was isolated from ovotestes of 40 snails, partially digested with HindIII, and ligated into pAGIBAC1 vector. The resulting B. glabrata BAC library (BG_BBa) consists of 61824 clones (136.3 kb average insert size) and provides 9.05 × coverage of the 931 Mb genome. Probing with single/low copy number genes from B. glabrata and fingerprinting of selected BAC clones indicated that the BAC library sufficiently represents the gene complement. BAC end sequence data (514 reads, 299860 nt) indicated that the genome of B. glabrata contains ~ 63% AT, and disclosed several novel genes, transposable elements, and groups of high frequency sequence elements. This BG_BBa BAC library, available from AGI at cost to the research community, gains in relevance because BB02 strain B. glabrata is targeted whole genome sequencing by NHGRI.