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The organization and structure of the national institutes of health.

In the assessment of domestic federal programs and the agencies responsible for them, few have been as frequently and highly praised as the National Institutes of Health (NIH). Contributing to that success in part is an unusual organization and structure. Based on a series of semiautonomous, disease-oriented program divisions supplemented by several support units with a co-ordinative function performed by the Director, NIH, a remarkable and essential combination of administrative stability and flexibility, as well as scientific and political acceptability, has emerged. The changing environment in which NIH now functions, however, suggests the need for a greater degree of intra-NIH and extra-NIH program integration and co-ordination. Concomitantly, there must be more consistent federal policies, a clearer definition and understanding of "technology transfer" and additional resources for the directors of NIH and the individual Institutes.

Financing, Government↗

CEACAM1-4S, a cell-cell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture.

In a 3D model of breast morphogenesis, CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) plays an essential role in lumen formation in a subline of the nonmalignant human breast cell line (MCF10A). We show that mammary carcinoma cells (MCF7), which do not express CEACAM1 or form lumena when grown in Matrigel, are restored to a normal morphogenic program when transfected with CEACAM1-4S, the short cytoplasmic isoform of CEACAM1 that predominates in breast epithelia. During the time course of lumen formation, CEACAM1-4S was found initially between the cells, and in mature acini, it was found exclusively in an apical location, identical to its expression pattern in normal breast. Lumena were formed by apoptosis as opposed to necrosis of the central cells within the alveolar structures, and apoptotic cells within the lumena expressed CEACAM1-4S. Dying cells exhibited classical hallmarks of apoptosis, including nuclear condensation, membrane blebbing, caspase activation, and DNA laddering. Apoptosis was mediated by Bax translocation to the mitochondria and release of cytochrome c into the cytoplasm, and was partially inhibited by culturing cells with caspase inhibitors. The dynamic changes in CEACAM1 expression during morphogenesis, together with studies implicating extracellular matrix and integrin signaling, suggest that a morphogenic program integrates cell-cell and cell-extracellular matrix signaling to produce the lumena in mammary glands. This report reveals a function of CEACAM1-4S relevant to cellular physiology that distinguishes it from its related long cytoplasmic domain isoform.

Antigens, CD↗

A high-resolution annotated physical map of the human chromosome 13q12-13 region containing the breast cancer susceptibility locus BRCA2.

Various types of physical mapping data were assembled by developing a set of computer programs (Integrated Mapping Package) to derive a detailed, annotated map of a 4-Mb region of human chromosome 13 that includes the BRCA2 locus. The final assembly consists of a yeast artificial chromosome (YAC) contig with 42 members spanning the 13q12-13 region and aligned contigs of 399 cosmids established by cross-hybridization between the cosmids, which were selected from a chromosome 13-specific cosmid library using inter-Alu PCR probes from the YACs. The end sequences of 60 cosmids spaced nearly evenly across the map were used to generate sequence-tagged sites (STSs), which were mapped to the YACs by PCR. A contig framework was generated by STS content mapping, and the map was assembled on this scaffold. Additional annotation was provided by 72 expressed sequences and 10 genetic markers that were positioned on the map by hybridization to cosmids.

BRCA2 Protein↗

Attitudes of preschool children toward their peers with disabilities: a year-long investigation in integrated classrooms.

Changes in choices of preferred playmates by 3- and 4-year-old children were observed over the course of a school year. All of the children in this study participated in planned, fully mainstreamed, same-age preschool classes. Sociometric assessments were obtained from all children without disabilities in October, February, and May of the school year; peer nominations of three "best friends" were obtained at the beginning and end of the school year. The 3-year-old children showed a general decline in the ratings given to all of their peers over the course of the school year. Four-year-old children showed significant preferences for same-sex peers without disabilities as playmates. The implications of these findings for integrated programs are discussed.

Attitude↗

RankGene: identification of diagnostic genes based on expression data.

RankGene is a program for analyzing gene expression data and computing diagnostic genes based on their predictive power in distinguishing between different types of samples. The program integrates into one system a variety of popular ranking criteria, ranging from the traditional t-statistic to one-dimensional support vector machines. This flexibility makes RankGene a useful tool in gene expression analysis and feature selection.

Algorithms↗

NdPASA: a pairwise sequence alignment server for distantly related proteins.

SUMMARY: NdPASA is a web server specifically designed to optimize sequence alignment between distantly related proteins. The program integrates structure information of the template sequence into a global alignment algorithm by employing neighbor-dependent propensities of amino acids as a unique parameter for alignment. NdPASA optimizes alignment by evaluating the likelihood of a residue pair in the query sequence matching against a corresponding residue pair adopting a particular secondary structure in the template sequence. NdPASA is most effective in aligning homologous proteins sharing low percentage of sequence identity. The server is designed to aid homologous protein structure modeling. A PSI-BLAST search engine was implemented to help users identify template candidates that are most appropriate for modeling the query sequences.

Algorithms↗

Intergenerational Partners Project: a model linking elementary students with senior center volunteers.

Age-integrated programming has become an effective way to bring the young and old closer together. This paper describes a 9-month intergenerational program designed to establish a more intimate involvement between a group of 4th graders and elderly volunteers from Senior Neighbors. The format used to organize the project is presented, and ongoing activities and program benefits are identified. The goals of this project have been richly met, reducing students' fears and misconceptions about aging and providing a satisfying experience for the seniors.

Aged↗

The Dutch Heart Health community intervention 'Hartslag Limburg': results of an effect study at individual level.

'Hartslag Limburg' (Dutch for Heartbeat Limburg), a regional cardiovascular diseases (CVD) prevention program, integrates a community strategy and a high-risk strategy to reduce CVD risk behaviors. The present paper focuses on the effects of the community intervention on fat intake and physical activity. The project was based on community organization principles and health education theories and methods. In order to implement the intervention, nine local Health Committees were set up, each organizing activities that facilitate and encourage people to adopt a healthier lifestyle. A pre-test-post-test control group design with two post-tests was used to evaluate the intervention. At baseline, representative random cohort research samples were selected in the Maastricht region and in a control region. Data on fat intake and physical activity, and on the psychosocial determinants of these behaviors, were gathered by means of mail surveys. The present study indicates that the intervention had a significant effect on fat reduction, especially among respondents aged <or=48 years (median age). Respondents in the Maastricht region were also more realistic about their fat intake at post-test as compared with the control region. Only a limited effect on intentions to increase physical activity was found.

Cardiovascular Diseases↗

Obesity prevention programs for children and youth: why are their results so modest?

The purpose of this paper is to critically reflect upon the mixed/modest results of the primary studies related to the effectiveness of physical activity enhancement and improving nutritional intake in obesity prevention programs for children and youth. The results of a recent review of this topic that included 57 randomized controlled trials provide the basis for this discussion. Only four primary studies reported both statistically and clinically significant outcome differences between intervention and comparison groups. Although there are some similarities, there are differences among the four studies. These differences relate to program duration, frequency and intensity, targeted age of participants and level of involvement of students, the school as a community/institution and parents. Frequent methodological limitations of the studies included inadequate sample selection, lack of masking of outcome assessors, inappropriate data analysis and lack of important sub-analyses. Program design and implementation issues included lack of monitoring of program integrity and 'dose' received by participants. Theoretical basis for interventions were rarely stated and never used to explain the results. The effectiveness of parental involvement is unclear. The question of statistical versus clinical significance needs to be addressed by clinical experts. Based on this reflection, several potential future directions are outlined.

Adolescent↗

Suppression of subadult Ixodes scapularis (Acari: Ixodidae) following removal of leaf litter.

Removal of leaf litter in wooded areas of a forested residential community significantly reduced the abundance of questing blacklegged tick, Ixodes scapularis Say, nymphs throughout their peak activity period. Removal of leaf litter, using hand rakes and leaf blowers during the early spring (March) and early summer (June) resulted in reductions in nymphal tick density ranging from 72.7 to 100%. Subsequent sampling of the I. scapularis population during the summer revealed similar rates of suppression of larvae. Although leaf removal provides levels of suppression similar to more traditional methods, including chemical acaricides, it is labor intensive and not free of possible nontarget effects. The potential role of leaf litter removal in an integrated program to control I. scapularis is discussed.

Animals↗

NRSub: a non-redundant data base for the Bacillus subtilis genome.

We have organized the DNA sequences of Bacillus subtillis from the EMBL collection to build the NRSub data base. This data base is free from duplications and all detected overlapping sequences are merged into contigs. Data on gene mapping and codon usage are also included. NRSub is publically available through anonymous FTP in flat file format or structured on the form of an ACNUC data base. Under this format, it is possible to use NRSub with the retrieval program Query--win. This program integrates a graphical interface and may be installed on any kind of UNX computer under X Window and on which the Vibrant and Motif libraries are available.

Bacillus subtilis↗

Dragon Gene Start Finder identifies approximate locations of the 5' ends of genes.

Recognition of gene starts is a difficult and yet unsolved problem. We present a program, Dragon Gene Start Finder (DGSF), which assesses the gene start in mammalian genomes and predicts a region which should overlap with the first exon of the gene or be in its proximity. The program has been rigorously tested on human chromosomes 4, 21 and 22, and in a strand specific search achieves an overall sensitivity of approximately 65% and a positive predictive value of approximately 78%. The sensitivity for the CpG-island related promoters is >88%. DGSF is free for academic and non-profit users at http://sdmc.lit.org.sg/promoter/dragonGSF1_0/genestart.htm; the download version of the program integrated within the TRANSPLORER package can be obtained from Biobase GmbH, at http://www.biobase.de/.

5' Flanking Region↗

Magnesium in drinking water and ischemic heart disease.

The associations found in the general populations of a number of different countries are suggestive and warrant an integrated program of laboratory and epidemiologic research to reject or confirm the magnesium-IHD hypothesis. Singling out this particular risk factor has two justifications. First, as would be the case with any epidemiologic risk factor for IHD whose attributable risk was large enough to be detectable through epidemiology, applying that attributable risk to the vast annual morbidity and mortality from IHD would translate into tens of thousands of lives benefited and millions of dollars in hospital costs avoided per year. Second, this particular risk factor could conceivably be eliminated by an inexpensive supplementation program. For example, a low-sodium, higher-magnesium and -potassium table salt has been recommended and used in Finland for many years, during a period when the prevalence of hypertension in population surveys was said to decrease (117). Interventions which do not require behavioral change have always been the most cost-effective in public health. We therefore urge funding agencies to give priority to studies determining whether there are unforeseen adverse effects of magnesium for some population subgroups and whether the apparent benefit derived from low doses of magnesium in the development of IHD or IHD death is real. Furthermore, researchers should determine which chemical form of magnesium is best absorbed and most effective. We need to better understand the interrelation of various water and food constituents, as well as individual risk factors, in the pathogenesis of IHD. Susceptible individuals who are at higher risk of being depleted of magnesium need to be identified, and potential untoward effects of magnesium should be studied. Future research must provide better answers about low level waterborne magnesium before recommendations to the public can be made.

Animals↗

Nutritional approaches to reducing phosphorus excretion by poultry.

Phosphorus is an essential mineral for growing poultry, and the consequences of a failure to provide for adequate quantities of this nutrient are physiologically and economically disastrous. Therefore, nutritionists provide a margin of safety for this mineral in their diets. However, because of growing concerns regarding the potential contribution of P in poultry excreta on eutrophication of surface waters, increasing pressure is being placed to limit the amount of excess P in diets and thus reduce fecal output. In order to significantly reduce fecal P while maintaining economic productivity, the nutritionist must establish and maintain an integrated program of activities, including an effective quality control program for incoming animal protein feeds, selection of P supplements of the highest biological value, use of phytase enzymes, and judicious selection of dietary P levels. Potential benefits of newer isomers of vitamin D and the commercial development of grains with high levels of nonphytate P offer promise in the future. Whatever measures are taken to increase the biological availability of the phytate-bound and nonphytate P portions of the diet, commensurate reductions in overall dietary P content must be made.

Agriculture↗