Comprehensive cardiopulmonary profile of individuals with Down syndrome.

BACKGROUND: Individuals with Down syndrome (DS) have low levels of cardiorespiratory fitness and previous studies have shown that these low levels of fitness have a physiological cause. During exercise, the cardiovascular, ventilatory and muscular systems are simultaneously active. While individual parameters of these systems have been investigated in DS before, the interaction between these parameters and systems have not been discussed in detail. Doing so may provide important insight regarding the aetiology of low cardiorespiratory fitness and which parameters of the cardiovascular, pulmonary and muscular systems are altered in individuals with DS compared with their peers without DS. METHODS: Cardiopulmonary exercise tests were performed in healthy adults with and without DS. Parameters related to the cardiovascular, ventilatory and muscular systems were collected until VO2peak . In total, 51 participants were included in analysis, of which 21 had DS. RESULTS: Individuals with DS showed lower peak values for all collected outcomes (P ≤ 0.001) compared with those without DS, except for ventilatory threshold as a percentage of maximal oxygen uptake and VE /VCO2 slope, which were similar. CONCLUSIONS: Our results show that individuals with DS present impairments across the cardiovascular, ventilatory and muscular aspects of the cardiopulmonary system.

Anthropometry does not fully explain low fitness among adults with Down syndrome.

BACKGROUND: Cardiorespiratory fitness, expressed as peak oxygen uptake during exercise (VO2 peak), is an important predictor of cardiovascular health and is related to anthropometry in the general population. Individuals with Down syndrome (DS) have reduced cardiorespiratory fitness and often exhibit different anthropometrics compared with the general population. Interestingly, the relation between anthropometry and cardiorespiratory fitness found in the general population is not apparent in individuals with DS. However, accurate measures with dual energy X-ray absorptiometry (DEXA) scan have not been used to investigate this relationship in this population. The purpose of this paper was to investigate the relationship between accurate measures of anthropometry and cardiorespiratory fitness in adults with DS compared with an age-matched and sex-matched control group. METHODS: Anthropometrics (height, weight, waist and hip circumference, body composition via DEXA) and cardiorespiratory fitness (VO2 peak, measured during a graded maximal exercise test) were assessed in adults with (n = 9; 25 ± 3 years; 6 male patients) and without DS (n = 10, 24 ± 4 years; 5 male patients). RESULTS: Participants with DS were shorter (P < 0.01) than without DS and had a higher body mass index (P < 0.01), waist circumference (WC) (P = 0.026) and waist/height ratio (WHtR) (P < 0.01), but similar weight, body surface area (BSA), waist/hip ratio and body composition (P > 0.05). Participants with DS had significantly lower relative VO2 peak and VO2 peak corrected for total lean mass (TLM), but similar absolute VO2 peak, compared with without DS. In participants with DS, only WC and WHtR were associated with VO2 peak, whereas in participants without DS, height, weight, BSA, TLM, leg lean mass and body fat percentage were associated with VO2 peak. CONCLUSIONS: These results suggest that the relation between anthropometry and cardiorespiratory fitness found in the general population is not the same in adults with DS and that anthropometrics do not fully explain cardiorespiratory fitness in adults with DS. Further research into potential alternative explanations is required.

Discovery of a novel Raf kinase inhibitor.

We discuss the biology of Ras signal transduction and the epidemiology of ras mutations in association with disease as a background for the development of a Raf kinase inhibitor, BAY 43-9006. Knowledge of Ras effector pathways has permitted genetic validation of numerous targets involved in the Ras signaling cascade. A key Ras effector pathway involves the kinase cascade RAF/MEK/ERK (MEK: MAP/ERK kinase; ERK: extracellular signal related kinase). Indeed, we present studies of cell lines stably expressing mutant MEK constructs, which point to Raf kinase as a target for therapeutics with selective anti-tumor activity. Finally, a small molecule drug discovery program based on inhibition of Raf kinase activity is outlined and the initial pre-clinical development process of the Raf kinase inhibitor BAY 43-9006 is discussed.

Shared T cell-defined antigens on independently derived tumors.

We report that a subset of tumors independently derived from a cloned line of contact-inhibited, non-tumorigenic murine fetal fibroblasts confer cross-protective immunity against each other in vivo. Concordant with the in vivo cross-protection, cytolytic T cell clones from mice immunized with one of these tumor lines specifically lyse the three other lines in the same set but do not cross-react with either the nontumorigenic parental line or another similarly derived tumor line representing a different antigenic profile. This and other recent evidence for shared expression of tumor rejection Ag contrasts with the antigenic diversity previously described for chemical- and radiation-induced tumors. In the interpretation of such data it is essential to distinguish between Ag expressed in association with the transformation process and Ag induced by random mutation of already transformed cells.

Sequence identity in an early chorion multigene family is the result of localized gene conversion.

The multigene families that encode the chorion (eggshell) of the silk moth, Bombyx mori, are closely linked on one chromosome. We report here the isolation and characterization of two segments, totaling 102 kb of genomic DNA, containing the genes expressed during the early period of choriogenesis. Most of these early genes can be divided into two multigene families, ErA and ErB, organized into five divergently transcribed ErA/ErB gene pairs. Nucleotide sequence identity in the major coding regions of the ErA genes was 96%, while nucleotide sequence identity for the ErB major coding regions was only 63%. Selection pressure on the encoded proteins cannot explain this difference in the level of sequence conservation between the ErA and ErB gene families, since when only fourfold redundant codon positions are considered, the divergence within the ErA genes is 8%, while the divergence within the ErB genes (corrected for multiple substitutions at the same site) is 110%. The high sequence identity of the ErA major exons can be explained by sequence exchange events similar to gene conversion localized to the major exon of the ErA genes. These gene conversions are correlated with the presence of clustered copies of the nucleotide sequence GGXGGX, encoding paired glycine residues. This sequence has previously been correlated with gradients of gene conversion that extend throughout the coding and noncoding regions of the High-cysteine (Hc) chorion genes of B. mori. We suggest that the difference in the extent of the conversion tracts in these gene families reflects a tendency for these recombination events to become localized over time to the protein encoding regions of the major exons.

Organization and expression of three genes from the silkmoth early chorion locus.

Chorion genes in the silkmoth Bombyx mori are clustered in a small region of one chromosome. Genes are grouped within this locus according to their expression in either early, middle, or late stages of choriogenesis. The entire set of late genes and a large fraction of the middle genes have been cloned and extensively characterized. We report here the first molecular characterization of a set of early chorion genes clustered within a 22.5-kb region. Transcripts homologous to these genes appear in the very first choriogenic follicle but disappear with different kinetics. One of the three early genes, 5H4, is the first example of a chorion gene which is not a member of a multigene family, or divergently paired with another chorion gene. The other two early genes, (ErA.1 and ErB.1) are divergently paired with each other in the manner of the middle and late chorion genes. The common 5' region between ErA.1 and ErB.1 is significantly shorter and does not contain certain sequence elements shared by the highly conserved 5' regions of middle and late chorion gene pairs. This evidence taken together with the fact that 5H4 is unpaired indicates that the early genes may utilize a regulatory mechanism somewhat different from the middle and late gene families.