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Large-scale hemizygous loss of chromosome 3p is a common event in neuroblastoma, occurring preferentially in tumors that exhibit loss of chromosome 11q and lack MYCN amplification. Although numerous tumor suppressor genes (TSG) have been mapped to the 3p region, the gene or genes contributing to neuroblastoma pathogenesis have remained elusive. High-resolution oligonucleotide array CGH mapping of chromosome 3p breakpoints relative to the positions of known TSGs indicates that more than one gene may contribute to neuroblastoma pathogenesis. We evaluated the methylation status of semaphorin 3B (SEMA3B), one of the chromosome 3p TSGs, in neuroblastoma tumors with (n = 12) and without (n = 32) 3p deletions. A significantly higher percentage of methylated CpG sites in the SEMA3B promoter was detected in tumors exhibiting 3p loss (95%), relative to tumors without loss (52%), suggestive of a two-hit mechanism of allele inactivation. The involvement of methylation in the control of SEMA3B expression was confirmed by treatment of neuroblastoma cell lines with the demethylating agent 5-aza-2-deoxycytidine. Transcriptional regulation of this locus is complex, however; low levels of SEMA3B expression were also seen in tumors with unmethylated SEMA3B promoters (n = 4). SEMA3B is known to play an important role in the development of normal sympathetic neurons, and interestingly, we found higher levels of SEMA3B expression in differentiated tumors with favorable histopathology (n = 19) than in tumors with unfavorable histology (n = 22). Furthermore, SEMA3B was upregulated in the SK-N-BE neuroblastoma cell line following induction of differentiation with retinoic acid. The association of SEMA3B expression with neuroblastoma differentiation suggests that this TSG may play a role in neuroblastoma pathobiology.

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate species in biomedical research. To create new opportunities for genetic and genomic studies using rhesus monkeys, we constructed a genetic linkage map of the rhesus genome. This map consists of 241 microsatellite loci, all previously mapped in the human genome. These polymorphisms were genotyped in five pedigrees of rhesus monkeys totaling 865 animals. The resulting linkage map covers 2048 cM including all 20 rhesus autosomes, with average spacing between markers of 9.3 cM. Average heterozygosity among those markers is 0.73. This linkage map provides new comparative information concerning locus order and interlocus distances in humans and rhesus monkeys. The map will facilitate whole-genome linkage screens to locate quantitative trait loci (QTLs) that influence individual variation in phenotypic traits related to basic primate anatomy, physiology, and behavior, as well as QTLs relevant to risk factors for human disease.

What is involved in creating learning environments for the 21st century? How can school facilities serve as tools for teaching and meet the needs of students in the future? What components are required to design effective schools, and how does architecture relate to the purposes of schooling? These are some of the questions addressed at the seminar on "Creating 21st Century Learning Environments" organised by the United Kingdom’s Department for Education and Skills and the OECD Programme on Educational Building (PEB). The answers provided by four people with first-hand experience in building schools are summarised here. A development and management professional explains how the school building can serve as a three-dimensional learning tool. A school principal describes how his recently-built public school in New Zealand was designed to meet the learning needs of 21st century students. A building planner presents what he considers the essential components for developing effective facilities for tomorrow, supported by his own experience in planning schools. Finally, the director of an architectural firm defines the common purposes of secondary schooling and their relation to design.

Qu’implique la creation d’environnements d’apprentissage pour le XXIe siecle ? Comment les installations scolaires peuvent-elles servir d’outils pedagogiques et repondre aux besoins des eleves dans le futur ? Quels elements sont necessaires pour concevoir des etablissements efficaces et comment l’architecture reflete-t-elle les besoins educatifs ? Ce sont la quelques-unes des questions qui ont ete traitees pendant le seminaire sur le theme « Concevoir les environnements d’apprentissage du XXIe siecle » organise par le ministere britannique de l’Education et des Competences (DfES) et le Programme de l’OCDE pour la construction et l’equipement de l’education (PEB). Les reponses a ces questions, apportees par quatre experts de la construction de bâtiments scolaires, sont resumees ci-apres. Un professionnel en conception et gestion explique comment un bâtiment scolaire peut servir d’outil pedagogique tridimensionnel. Un directeur d’etablissement public en Nouvelle-Zelande decrit la facon dont son ecole recemment construite a ete concue pour repondre aux besoins pedagogiques des eleves du XXIe siecle. Un specialiste en planification de la construction presente ce qu’il considere comme des elements essentiels a la conception d’installations efficaces pour le futur, en s’appuyant sur sa propre experience en matiere de planification d’etablissements scolaires. Enfin, le directeur d’un cabinet d’architectes definit les objectifs de l’enseignement secondaire et leur lien avec la conception.

To examine the relationship between body mass and gastro-oesophageal reflux in a large population-representative sample from the UK.Cross-sectional population-based study, as part of a randomized controlled trial of eradication of Helicobacter pylori infection, in Southwest England. Subjects In all, 10 537 subjects, aged 20-59 years, were recruited from seven general practices. Subjects provided data on frequency and severity of dyspeptic symptoms and anthropometric measurements were taken.Relationship between overweight (body mass index [BMI]/=25 kg/m(2) and/=30 kg/m(2)) or obesity (BMI30 kg/m(2)) and frequency and severity of heartburn and acid regurgitation.Body mass index was strongly positively related to the frequency of symptoms of gastro-oesophageal reflux. The adjusted odds ratios (OR) for frequency of heartburn and acid regurgitation occurring at least once a week in overweight participants compared with those of normal weight were 1.82 (95% CI: 1.33-2.50) and 1.50 (95% CI: 1.13-1.99) respectively. Corresponding OR (95% CI) relating to obese patients were 2.91 (95% CI: 2.07-4.08) and 2.23 (95% CI: 1.44-3.45) respectively. The OR for moderate to severe reflux symptoms were raised in overweight and obese subjects but not to the same extent as frequency of symptoms and only the relationship between obesity and severity of heartburn reached conventional statistical significance: OR = 1.19; 95% CI: 1.07-1.33.Being above normal weight substantially increases the likelihood of suffering from heartburn and acid regurgitation and obese people are almost three times as likely to experience these symptoms as those of normal weight.

Background: Helicobacter‐pylori ‐related duodenal ulcer (DU) is an important cause of dyspepsia. Aim: To determine the relationship between the pattern of H. pylori infection and the epidemiology of duodenal ulcer in a single population. Design: Prospective two‐part study of (i) patients with DU referred for endoscopy because of dyspepsia, and (ii) the incidence of H. pylori infection in the general population of the same area. Methods: Details of 533 DU patients were recorded, and related to the pattern of H. pylori infection among 10 537 adults in the same community, determined by the [13][1]C‐urea breath test. Results: In patients with DU, birth year was more important than age in determining the rate of presentation for endoscopy (the ‘birth cohort’ effect). H. pylori infection showed a similar birth cohort effect, and the prevalence decreased steadily in those born in successive years, from 28.8% in the 1930s to 3.5% in the 1970s. The proportion of dyspeptic patients who had duodenal ulcers also fell progressively, from 22.2% in 1979 to 5.7% in 1998. H. pylori prevalence and duodenal ulcer incidence were closely correlated at all ages. Discussion: Duodenal ulcer prevalence (as judged by the rate of referral of duodenal ulcer patients for endoscopy) is determined principally by the distribution of H. pylori infection in the local population. The birth cohort effect seen in adult duodenal ulcer patients reflects the acquisition of H. pylori in childhood. In Bristol, H. pylori prevalence and duodenal ulcer incidence are both declining to very low levels. [1]: #ref-13

The Bristol Helicobacter Project is an ongoing, pragmatic, double-blind placebo-controlled trial of the effect of Helicobacter pylori eradication on symptoms of dyspepsia, health utilization and costs, and quality of life in the adult population. Commencing in 1996, 27,536 individuals ages 20-59 years who were registered with seven primary care centers in Bristol and the surrounding areas in southwest England were invited to undergo a 13C urea breath test. There was no selection on the basis of symptoms and 23.5% had dyspepsia on entry to the study. A total of 10,537 people were tested (38.3% of those invited), 1636 tested positive (15.5% of those tested), and 1558 (95.2% of those who tested positive) were randomized to H. pylori eradication therapy or placebo. The rate of participation in the screening phase increased with age (odds ratio [OR]: 1.42 per decade, 95% CI: 1.31 to 1.54) and female gender (OR: 1.35, 95% CI: 1.27 to 1.43) but decreased with lower socioeconomic status (OR: 0.70, 95% CI: 0.56 to 0.86 comparing lowest with highest category). H. pylori prevalence increased with age (OR: 1.69 per decade, 95% CI: 1.51 to 1.89) and lower socioeconomic status (OR: 1.33, 95% CI: 1.05 to 1.69) but was lower in women (OR: 0.87, 95% CI: 0.76 to 1.00). Population-based trials of H. pylori eradication are feasible but necessitate screening large numbers of people to identify those who are infected and who may benefit from eradication. In the Bristol Helicobacter Project the rate of participation varied inversely with both social deprivation and the prevalence of the infection.

In the present study we investigated the mechanisms responsible for and the biological consequences of the constitutive activation of the insulin-like growth factor-1 receptor (IGF-1R) in the MIA PaCa-2 cells. An aberrant increase in the expression and activation of the IGF-1R was observed during the transition of growth states from exponential to quiescent. The increase in IGF-1R expression is preceded by an increase in IGF-1R mRNA transcript and is associated with an increase in the IGF-1R promoter activity. Inhibition of de novo transcription by actinomycin D increased the stability of IGF-1R mRNA in exponentially growing cells, thereby increasing the expression of IGF-1R to a level similar to that seen in quiescent cells. Increased IGF-1R signaling mediated the growth factor independence of quiescent MIA PaCa-2 cells through the constitutive activation of mitogen-activated protein kinase (MAPK). Exogenous IGF-1 increased cell proliferation and activated MAPK and AKT signaling pathways. The resistance of cells to apoptosis by IGF-1R signaling was mediated through MAPK and phosphatidylinositol 3-kinase (PI3K) pathways and a yet unidentified pathway(s). Thus, aberrant regulation of IGF-1R signaling is required for resistance to apoptosis and growth factor independence of MIA PaCa-2 cells. This likely protects cells from unfavorable conditions and allows cells to rapidly re-enter the cell cycle when conditions are favorable.

Prakash Nair of the United States proposes the list below for evaluating how a school measures up to the most important requirements of the 21st century. It addresses architects, administrators, head teachers, pupils and others responsible for or interested in the design of a new school or the renovation of an existing building.

Cet article est un compte rendu de l’atelier de travail sur le Temps organise dans le cadre de la conference internationale « Des environnements pedagogiques novateurs » qui s’est tenue en novembre 2000. Ce compte rendu, redige par Prakash Nair, expert americain en installations et techniques scolaires, beneficie fortement de la contribution de Hans F. Van Aalst, co-dirigeant de l’atelier de travail, et de tous les participants concernes.

Prakash Nair (Etats-Unis) propose la liste ci-dessous pour evaluer dans quelle mesure un etablissement satisfait aux principales exigences de l’ecole du XXIe siecle. Il s’adresse aux architectes, administrateurs, directeurs d’ecole, eleves et autres personnes responsables de la construction d’une nouvelle ecole ou de la rehabilitation d’un bâtiment ou interesses par elles.

PEB co-hosted a symposium entitled “Invention, Maintenance, and Renewal of Urban Educational Facilities: Global Challenges and Community Solutions” with the American Institute of Architects’ Committee on Architecture for Education and the CEFPI Urban Education Facilities NE Chapter in October 1999. The meeting aimed to provide arguments and evidence for system managers seeking to secure resources for maintenance as well as to sharpen their abilities to use those resources well. Below are excerpts from the symposium papers, including keynote presentations and workshop reports.

What follows is an edited transcript of an interview with Glenn Meeks and Prakash Nair by Randall Fielding, U.S. architect and planner, contributing editor to "School Construction News" and the editor of "Design Share".

Ceramide manifests both neurotoxic and neuroprotective properties depending on the experimental system. Ito and Horigome previously reported that ceramide delays apoptosis in a classic model of developmental programmed cell death, i.e. sympathetic neurons undergoing NGF deprivation.1 Here, we investigated the actions of ceramide upon the biochemical and genetic changes that occur in NGF deprived neurons. We correlate ceramide's neuroprotective actions with the ability of ceramide to antagonize NGF deprivation-induced oxidative stress and c-jun induction, both of which contribute to apoptosis in this model. However, ceramide did not block NGF deprivation-induced declines in RNA and protein synthesis, suggesting that ceramide does not slow all apoptosis-related events. Overall, these results are significant in that they show that ceramide acts early in the death cascade to antagonize two events necessary for NGF-deprivation induced neuronal apoptosis. Moreover, these results dissociate declines in neuronal function, i.e. macromolecular synthesis, from the neuronal death cascade.

En octobre 1999, le PEB a organise un seminaire intitule « Creation, maintenance et renouvellement des equipements educatifs en milieu urbain : enjeux globaux et solutions locales », en collaboration avec le Committee on Architecture for Education de l’American Institute of Architects et avec l’Urban Educational Facilities NE Chapter du CEFPI (la section nord-est du CEFPI consacree aux equipements educatifs en milieu urbain). L’objectif de ce seminaire etait de fournir des arguments et des temoignages aux gestionnaires des systemes cherchant a mobiliser des ressources pour l’entretien des equipements, et de renforcer leur aptitude a bien utiliser ces ressources. Vous trouverez ci-dessous des extraits du rapport du seminaire, comprenant des interventions, ainsi que les conclusions de certains travaux de groupes.

In this study, I use panel data from the Nepal Living Standards Survey to investigate the impact of gender and remittances on household expenditure patterns in Nepal between 1995/96 and 2003/04. Using a Working-Leser model, I show that both the gender of the remitter and that of the recipient have an effect on the share of the household budget devoted to schooling, consumer goods, health, durable goods and food, and that these effects are individually and jointly statistically significant. When the sample is restricted to only those households which receive remittances, I show that the budget share devoted to schooling, health and durable goods increases, and that devoted to food decreases, when remittances both are sent and received by women. These results support existing literature on migrant behavior and intra-household bargaining models and show that increased female migration and remittances would contribute positively to both economic and human development in Nepal.

Alzheimer's disease (AD) has been hypothesized to be associated with oxidative stress. In this study, the expression of key oxidative stress-handling genes was studied in hippocampus, inferior parietal lobule, and cerebellum of 10 AD subjects and 10 control subjects using reverse transcriptase-polymerase chain reaction (RT-PCR). The content of Mn-, Cu,Zn-superoxide dismutases (Mn- and Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) mRNAs, and the "marker genes" (beta-actin and cyclophilin) mRNAs was determined. This study suggests that gene responses to oxidative stress can be significantly modulated by the general decrease of transcription in the AD brain. To determine if the particular oxidative stress handling gene transcription was induced or suppressed in AD, the "oxidative stress-handling gene/beta-actin" ratios were quantified and compared with control values in all brain regions studied. The Mn-SOD mRNA/beta-actin mRNA ratio was unchanged in all regions of the AD brain studied, but an increase of the Cu,Zn-SOD mRNA/beta-actin mRNA ratio was observed in the AD inferior parietal lobule. The levels of peroxidation handling (CAT, GSHPx, and GSSG-R) mRNAs normalized to beta-actin mRNA level were elevated in hippocampus and inferior parietal lobule, but not in cerebellum of AD patients, which may reflect the protective gene response to the increased peroxidation in the brain regions showing severe AD pathology. The results of this study suggest that region-specific differences of the magnitude of ROS-mediated injury rather than primary deficits of oxidative stress handling gene transcription are likely to contribute to the variable intensity of neurodegeneration in different areas of AD brain.

The early growth response-1 (EGR-1) protein is an anti-proliferative signal for certain tumor cells and is required for apoptosis induced by stimuli that elevate intracellular Ca2+. We present evidence that EGR-1 transactivates the promoter of the p53 gene and up-regulates p53 RNA and protein levels. Inhibition of p53 function with dominant-negative p53 mutants abrogates EGR-1-dependent apoptosis. These findings establish a direct functional link between EGR-1 and the p53-mediated cell death pathway and suggest that mutant forms of p53 in tumor cells may provide resistance to the anti-proliferative effects of EGR-1.

The prostate apoptosis response-4 (par-4) gene was identified by differential screening for genes that are upregulated when prostate cancer cells are induced to undergo apoptosis. The par-4 gene is induced by apoptotic signals but not by growth-arresting, necrotic, or growth-stimulatory signals. The deduced amino acid sequence of par-4 predicts a protein with a leucine zipper domain at its carboxy terminus. We have recently shown that the Par-4 protein binds, via its leucine zipper domain, to the zinc finger domain of Wilms' tumor protein WT1 (R. W. Johnstone et al., Mol. Cell. Biol. 16:6945-6956, 1996). In experiments aimed at determining the functional role of par-4 in apoptosis, an antisense par-4 oligomer abrogated par-4 expression and activator-driven apoptosis in rat prostate cancer cell line AT-3, suggesting that par-4 is required for apoptosis in these cells. Consistent with a functional role for par-4 in apoptosis, ectopic overexpression of par-4 in prostate cancer cell line PC-3 and melanoma cell line A375-C6 conferred supersensitivity to apoptotic stimuli. Transfection studies with deletion mutants of Par-4 revealed that full-length Par-4, but not mutants that lacked the leucine zipper domain of Par-4, conferred enhanced sensitivity to apoptotic stimuli. Most importantly, ectopic coexpression of the leucine zipper domain of Par-4 inhibited the ability of Par-4 to enhance apoptosis. Finally, ectopic expression of WT1 attenuated apoptosis, and coexpression of Par-4 but not a leucine zipperless mutant of Par-4 rescued the cells from the antiapoptotic effect of WT1. These findings suggest that the leucine zipper domain is required for the Par-4 protein to function in apoptosis.

Induction of apoptosis by diverse exogenous signals is dependent on elevation of intracellular Ca2+. This process of cell death can be blocked by actinomycin D, indicating that it requires gene transcription events. To identify genes that are required for apoptosis, we used thapsigargin (TG), which inhibits endoplasmic reticulum-dependent Ca(2+)-ATPase and thereby increases cytosolic Ca2+. Exposure to TG led to induction of the zinc finger transcription factor, EGR-1, and apoptosis in human melanoma cells, A375-C6. To determine the functional relevance of EGR-1 expression in TG-inducible apoptosis, we employed a dominant negative mutant which functionally competes with EGR-1 in these cells. Interestingly, the dominant negative mutant inhibited TG-inducible apoptosis. Consistent with this observation, an antisense oligomer directed against Egr-1 also led to a diminution of the number of cells that undergo TG-inducible apoptosis. These results suggest a novel regulatory role for EGR-1 in mediating apoptosis that is induced by intracellular Ca2+ elevation. We have previously shown that in these melanoma cells, EGR-1 acts to inhibit the growth arresting action of interleukin-1. Together, these results imply that EGR-1 plays inducer-specific roles in growth control.

Background: Diverse tumors in the posterior third ventricular region (TPTVR) frequently occur in children. A decade's experience with pediatric TPTVR is presented, focusing on the Indian perspective. Materials and Methods: 25 children (age range: 3-18 years; mean age: 13.32 years; presentation range: 7 days-2.5 years) had clinico-radiological assessment with contrast computed tomography (CT) and magnetic resonance imaging (MRI). The ventricular/lumbar cerebrospinal fluid (CSF) alpha feto protein (AFP)/beta human chorionic gonadotrophin (HCG) estimation was done when radiological suspicion of a germ cell tumor was present. Extent of resection was deemed partial when some tumor mass remained at the end of surgery, near total when

Many studies have reported an association between Helicobacter pylori infection and an increased risk of cardiovascular disease. The strength of the association has been hard to judge because of the varied methods of the studies and substantial heterogeneity of the findings. Mechanisms that may contribute to this association include abnormalities in the levels of certain blood proteins (for example fibrinogen or C reactive protein) secondary to the chronic infection 1 2 and raised blood pressure in people infected with H pylori .3–5 There are several methodological difficulties in carrying out studies to determine whether H pylori infection results in raised blood pressure. We have attempted to minimise such problems in a large prospective community based study of the association between H pylori infection and blood pressure. The Bristol helicobacter project is a community based study centred on the northeastern suburbs of Bristol. The primary aims of the study are to assess the …

Objectives To investigate the effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux. Design Cross sectional study, followed by a randomised placebo controlled trial. Setting Seven general practices in Bristol, England. Participants 10 537 people, aged 20-59 years, with and without H pylori infection (determined by the 13C-urea breath test). Main outcome measures Prevalence of heartburn and gastro-oesophageal acid reflux at baseline and two years after treatment to eradicate H pylori infection. Results At baseline, H pylori infection was associated with increased prevalence of heartburn (odds ratio 1.14, 95% confidence interval 1.05 to 1.23) but not reflux (1.05, 0.97 to 1.14). In participants with H pylori infection, active treatment had no effect on the overall prevalence of heartburn (0.99, 0.88 to 1.12) or reflux (1.04, 0.91 to 1.19) and did not improve pre-existing symptoms of heartburn or reflux. Conclusions H pylori infection is associated with a slightly increased prevalence of heartburn but not reflux. Treatment to eradicate H pylori has no net benefit in patients with heartburn or gastro-oesophageal reflux.