The period of early recovery after exercise is characterized by a rapid payback of the oxygen debt incurred during exercise. The purpose of this study was to test the hypothesis that the oxygen ...consumption (VO(2)) decline during the first minute of recovery after exercise will be faster in children with a higher peak VO(2).
We performed a clinically indicated bicycle exercise test in 203 children, aged 15.5 ± 3.2 yr; 33 had healthy heart/minimal heart disease, 59 had left-sided heart disease, 92 had right-sided heart disease, and 19 had postoperative single ventricle. VO(2) was recorded at peak exercise and at 20, 40, and 60 s of recovery.
Peak VO(2) in the study cohort was 30.1 ± 8.5 mL·kg(-1)·min(-1) and fell to 24.3 ± 6.7, 19.5 ± 4.9, and 15.3 ± 4.0 mL·kg(-1)·min(-1) at 20, 40, and 60 s of recovery, respectively. VO(2) recovery was slower in children with right-sided heart disease and single ventricle compared with the other 2 groups and was faster in younger children, boys, children with a higher peak VO(2), and in those with a lower RER at peak exercise. In the linear regression analysis, the slope of VO(2) decline during the first minute of recovery was most strongly associated with the peak VO(2) (R(2) = 0.786, P < 0.001). The only other variable that added to the explained variance was peak RER (R(2) = 0.796, P = 0.004).
VO(2) decline during the first minute of recovery after maximum exercise is faster in children with higher peak VO(2). VO(2) recovery may be a useful tool in assessing cardiopulmonary health in children.
A significant difficulty faced by the pharmaceutical industry is the initial identification and selection of macromolecular targets upon which
de novo drug discovery programs can be initiated. A drug ...target should have several characteristics: known biological function; robust assay systems for
in vitro characterization and high-throughput screening; and be specifically modified by and accessible to small molecular weight compounds
in vivo. Ion channels have many of these attributes and can be viewed as suitable targets for small molecule drugs. Potassium (K
+) ion channels form a large and diverse gene family responsible for critical functions in numerous cell types, tissues and organs. Recent discoveries, facilitated by genomics technologies combined with advanced biophysical characterization methods, have identified novel K
+ channels that are involved in important physiologic processes, or mutated in human inherited disease. These findings, coupled with a rapidly growing body of information regarding modulatory channel subunits and high resolution channel structures, are providing the critical information necessary for validation of K
+ channels as drug targets.
Inflammatory bowel disease (IBD) is characterized by a chronic relapsing intestinal inflammation, typically starting in early adulthood. IBD is subdivided into two subtypes, on the basis of clinical ...and histologic features: Crohn disease and ulcerative colitis (UC). Previous genomewide searches identified regions harboring susceptibility loci on chromosomes 1, 3, 4, 7, 12, and 16. To expand our understanding of the genetic risk profile, we performed a 9-cM genomewide search for susceptibility loci in 268 families containing 353 affected sibling pairs. Previous linkages on chromosomes 12 and 16 were replicated, and the chromosome 4 linkage was extended in this sample. New suggestive evidence for autosomal linkages was observed on chromosomes 1, 6, 10, and 22, with LOD scores of 2.08, 2.07, 2.30, and 1.52, respectively. A maximum LOD score of 1.76 was observed on the X chromosome, for UC, which is consistent with the clinical association of IBD with Ullrich-Turner syndrome. The linkage finding on chromosome 6p is of interest, given the possible contribution of human leukocyte antigen and tumor necrosis–factor genes in IBD. This genomewide linkage scan, done with a large family cohort, has confirmed three previous IBD linkages and has provided evidence for five additional regions that may harbor IBD predisposition genes.
Inflammatory bowel disease (IBD) is a multifactorial disorder, with both genetic and environmental factors contributing to the two clinical phenotypes of Crohn's disease (CD) and ulcerative colitis ...(UC). The underlying genetic model is thought to involve multiple genes with complex interactions between disease loci, and the NOD2 gene on chromosome 16 has recently been identified as a CD susceptibility locus. Several genome-wide linkage studies have identified candidate regions, but there has been little replication across studies. Here we investigate the role of sex-specific loci in susceptibility to IBD. Linkage data from our previously reported genome search and follow-up study were stratified by the sex of the affected sib pair. Non-parametric linkage analysis was performed using Genehunter Plus. Simulation studies were used to assess the significance of differences in LOD scores between male and female families for each chromosome. Several regions of sex-specific linkage were identified, including existing and novel candidate loci. The major histocompatibility region on chromosome 6p, referred to as IBD3, showed evidence of male-specific linkage with a maximum LOD score of 5.9 in both CD and UC male-affected families. Regions on chromosomes 11, 14 and 18 showed strong evidence of linkage in male-affected families but not in female-affected families. No evidence of sex-specific linkage was found in the IBD1 or IBD2 candidate regions of chromosomes 16 and 12. The existence of sex-specific linkage is further evidence of the complex mechanisms involved in IBD and will facilitate future studies to identify susceptibility genes.
Long QT syndrome (LQT) is an autosomal dominant disorder that can cause sudden death from cardiac arrhythmias. We recently discovered that mutations in HERG, a K+-channel gene, cause chromosome ...7-linked LQT. Heterologous expression of HERG in Xenopus oocytes revealed that HERG current was similar to a well-characterized cardiac delayed rectifier K+ current, IKr, and led to the hypothesis that mutations in HERG reduced IKr, causing prolonged myocellular action potentials. To define the mechanism of LQT, we injected oocytes with mutant HERG complementary RNAs, either singly or in combination with wild-type complementary RNA. Some mutations caused loss of function, whereas others caused dominant negative suppression of HERG function. These mutations are predicted to cause a spectrum of diminished IKr and delayed ventricular repolarization, consistent with the prolonged QT interval observed in individuals with LQT.
Arachidonic acid (AA) is an important constituent of membrane phospholipids and can be liberated by activation of cellular phospholipases. AA modulates a variety of ion channels via diverse ...mechanisms, including both direct effects by AA itself and indirect actions through AA metabolites. Here, we report excitatory effects of AA on a cloned human inwardly rectifying K(+) channel, Kir2.3, which is highly expressed in the brain and heart and is critical in regulating cell excitability. AA potently and reversibly increased Kir2.3 current amplitudes in whole-cell and excised macro-patch recordings (maximal whole-cell response to AA was 258 +/- 21% of control, with an EC(50) value of 447 nM at -97 mV). This effect was apparently caused by an action of AA at an extracellular site and was not prevented by inhibitors of protein kinase C, free oxygen radicals, or AA metabolic pathways. Fatty acids that are not substrates for metabolism also potentiated Kir2.3 current. AA had no effect on the currents flowing through Kir2.1, Kir2.2, or Kir2.4 channels. Experiments with Kir2.1/2.3 chimeras suggested that, although AA may bind to both Kir2.1 and Kir2.3, the transmembrane and/or intracellular domains of Kir2.3 were essential for channel potentiation. These results argue for a direct mechanism of AA modulation of Kir2.3.
Background & Aims: Inflammatory bowel disease (IBD) is a complex disorder of unknown etiology. Epidemiological investigations suggest a genetic basis for IBD. Recent genetic studies have identified ...several IBD linkages. The significance of these linkages will be determined by studies in large patient collections. The aim of this study was to replicate IBD linkages on chromosomes 12 and 16 in a large European cohort.
Methods: Three hundred fifty-nine affected sibling pairs from 274 kindreds were genotyped using microsatellite markers spanning chromosomes 12 and 16. Affection status of the sibling pairs was defined as Crohn's disease (CD) or ulcerative colitis (UC).
Results: Nonparametric statistical analyses showed linkage for both chromosomes. Two-point results for chromosome 12 peaked at D12S303 (logarithm of odds LOD, 2.15;
P = 0.003) for CD and at D12S75 (LOD, 0.92;
P = 0.03) for UC. Multipoint analyses produced a peak LOD of 1.8 for CD. Chromosome 16 showed linkage for CD at marker D16S415 (LOD, 1.52;
P = 0.007). Multi-point support peaked above markers D16S409 and D16S411 (LOD, 1.7).
Conclusions: These data are consistent with linkage of IBD to chromosomes 12 and 16. The replication of genetic risk loci in a large independent family collection indicates important and common susceptibility genes in these regions and will facilitate identification of genes involved in IBD.
GASTROENTEROLOGY 1998;115:1066-1071
To identify genes involved in vascular disease, we investigated patients with supravalvular aortic stenosis (SVAS), an inherited vascular disorder that causes hemodynamically significant narrowing of ...large elastic arteries. Pulsed-field gel and Southern analyses showed that a translocation near the elastin gene cosegregated with SVAS in one family. DNA sequence analyses demonstrated that the translocation disrupted the elastin gene and localized the breakpoint to exon 28. Taken together with our previous study linking SVAS to the elastin gene in two additional families and existing knowledge of vascular biology, these data suggest that mutations in the elastin gene can cause SVAS.
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