ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

In recent years, impressive advances have occurred in our understanding of transcriptional regulation of cardiac development. These insights have begun to elucidate the mystery of congenital heart disease at the molecular level. In addition, the molecular pathways emerging from the study of cardiac development are being applied to the understanding of adult cardiac disease. Preliminary results support the contention that a thorough understanding of molecular programs governing cardiac morphogenesis will provide important insights into the pathogenesis of human cardiac diseases. This review will focus on examples of transcription factors that play critical roles at various phases of cardiac development and their relevance to cardiac disease. This is an exciting and burgeoning area of investigation. It is not possible to be all-inclusive, and the reader will note important efforts in the areas of cardiomyocyte determination, left-right asymmetry, cardiac muscular dystrophies, electrophysiology and vascular disease are not covered. For a more complete discussion, the reader is referred to recent reviews including the excellent compilation of observations assembled by Harvey and Rosenthal (1).

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Neuronal migration appears as a complex ontogenic step occurring early during embryonic and fetal development. Control of neuronal migration involves different cell populations including Cajal-Retzius neurons, subplate neurons, neuronal precursors or radial glia. The integrity of multiple molecular mechanisms, such as cell cycle control, cell-cell adhesion, interaction with extracellular matrix protein, neurotransmitter release, growth factor availability, platelet-activating factor degradation or transduction pathways seems to be critical for normal neuronal migration. The complexity and the multiplicity of these mechanisms probably explain the clinical, radiologic and genetic heterogeneity of human disorders of neuronal migration. The present review will be focused on mechanisms and disturbances of migration of neurons destined to the neocortex. New insights gained from the analysis of animal models as well as from the study of human diseases will be included.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The variability in intestinal disease severity in patients with cystic fibrosis (CF) has been associated with the expression of secondary modifier genes. The locus containing these modifier genes in CF patients is syntenic with a modifier locus previously associated with survival in CF transmembrane conductance regulator–knockout mice. These previous studies showed that the proportion of CF mice that survive weaning (mildly affected mice)versusthose that succumb to obstruction of the small intestine (severely affected) is related to their genetic background and the expression of modifier genes. In the present work, we show that the basal transepithelial chloride transport measured across jejuna obtained from mice of mixed genetic backgrounds segregates into two groups, some mice having low and others having high, near normal chloride transport. Further, we report that the segregation of mice with respect to intestinal chloride transport correlates with their predicted segregation on the basis of genotype at the “modifier locus.” These findings support the hypothesis that intestinal disease modification in CF mice correlates with improved chloride transport through non-CF transmembrane conductance regulator chloride channels.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The cosecretion of pancreatic lipase and colipase are important in normal fat digestion. As adsorption of phosphatidylcholine to the lipid substrate interferes with lipase activity, hydrolysis to lysophosphatidylcholine with subsequent desorption is also essential for fat digestion. There are some data regarding the secretion of pancreatic phospholipases in normal adults but none in children or patients with pancreatic disease. In the present study, we aimeda) to develop an accurate fast assay method to measure phospholipase A2andb) to determine the secretion rate of pancreatic phospholipase A2and whether it is cosecreted with lipase and colipase in children with exocrine pancreatic dysfunction. Nine male patients aged 0.5 to 16 y (seven with cystic fibrosis, two with malabsorption) underwent pancreatic stimulation tests. Their colipase and lipase secretion rates were measured by titrimetric methods and phospholipase A2and A1by phosphorus magnetic resonance spectroscopy (31P NMR). It was found that the phospholipases, colipase, and lipase were absent in the two patients with pancreatic insufficiency. In patients with normal absorption, there were marked inter-and intrasubject variations of lipase, colipase, and phospholipase secretion rates that were consistent with the degree of exocrine pancreatic dysfunction. However, in the three 20-min stimulation periods of the pancreatic function test, pancreatic phospholipase is cosecreted with lipase and colipase, and average colipase and phospholipase A2secretion rates follow a similar or parallel pattern. These findings are consistent with the important role of pancreatic phospholipases in intestinal phospholipid hydrolysis leading to the desorption of phospholipids from the lipid substrate and enhancing lipid hydrolysis and phospholipid absorption.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Staphylococcus aureushas been isolated at an increasing rate from infants’ stools during the last decades, but it is not known whether this species can colonize and persist in the intestinal microflora. To investigate this, 49 Swedish infants were followed prospectively from birth until 12 months of age.S. aureuswas identified in a rectal swab obtained 3 d after delivery and in quantitative cultures of fecal samples collected at 1, 2, 4, and 8 weeks and at 6 and 12 months of age. A random amplified polymorphic DNA (RAPD) method was developed to distinguish individualS. aureusstrains from one another and the strains were tested for production of enterotoxins A-D and TSST-1. By 3 days of age, 16% of infants hadS. aureusin their intestines, which increased to 73% by 2-6 months, whereafter it decreased slightly to 53%. At the same timeS. aureuspopulation counts in colonized infants declined from an average 106.8CFU/g feces during the first months of life to 104.0CFU/g feces by 12 months. Colonized infants usually harbored one or twoS. aureusstrains in their microflora for long periods of time. Few strains were transient passengers and the median time of persistence ofS. aureusstrains in the microflora was several months. Of the 75S. aureusstrains identified, 43% produced one or more toxins: 13% SEA, 7% SEB, 23% SEC, 4% SED, and 11% TSST-1. Altogether, 47% of the investigated infants were colonized by a toxin-producingS. aureusduring their first year of life. Despite this they were apparently healthy and did not have more gastrointestinal problems than noncolonized infants. This report is the first to show thatS. aureusmay be a resident member of the normal intestinal microflora in infancy.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The pyruvate dehydrogenase (PDH) complex is situated at a key position in energy metabolism and is responsible for the conversion of pyruvate to acetyl CoA. In the literature, two unrelated patients with a PDH complex deficiency and splicing out of exon 6 of the PDH E1&agr; gene have been described, although intronic/exonic boundaries on either side of exon 6 were completely normal. Analysis of exon 6 in genomic DNA of these patients revealed two exonic mutations, a silent and a missense mutation. Although not experimentally demonstrated, the authors in both publications suggested that the exonic mutations were responsible for the exon skipping. In this work, we were able to demonstrate, by performing splicing experiments, that the two exonic mutations described in the PDH E1&agr; gene lead to aberrant splicing. We observed a disruption of the predicted wild-type pre-mRNA secondary structure of exon 6 by the mutated sequences described. However, when we constructed mutations that either reverted or disrupted the wild-type predicted pre-mRNA secondary structure of exon 6, we were unable to establish a correlation between the aberrant splicing and disruption of the predicted structure. The mutagenic experiments described here and the silent mutation found in one of the patients suggest the presence of an exonic splicing enhancer in the middle region of exon 6 of the PDH E1&agr; gene.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Gitelman syndrome is an inherited renal disorder characterized by impaired NaCl reabsorption in the distal convoluted tubule and secondary hypokalemic alkalosis. In clinical practice, it is distinguished from other hypokalemic tubulopathies by the presence of both hypomagnesemia and normocalcemic hypocalciuria. To date, only mutations in a single gene encoding the thiazide-sensitive NaCl cotransporter have been found as the molecular basis of GS. We describe three unrelated patients presenting with the typical laboratory findings of GS. Mutational analysis in these patients revealed no abnormality in theSLC12A3gene. Instead, all patients were found to carry previously described mutations in theCLCNKBgene, which encodes the kidney-specific chloride channel ClC-Kb, raising the possibility of genetic heterogeneity. Review of the medical histories revealed manifestation of the disease within the first year of life in all cases. Clinical presentation included episodes of dehydration, weakness, and failure to thrive, much more suggestive of classic Bartter syndrome than of GS. The coexistence of hypomagnesemia and hypocalciuria was not present from the beginning. In the follow-up, however, a drop of both parameters below normal range was a consistent finding reflecting a transition from cBS to GS phenotype. The phenotypic overlap may indicate a physiologic cooperation of the apical thiazide-sensitive NaCl cotransporter and the basolateral chloride channel for salt reabsorption in the distal convoluted tubule.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Nephrin is a novel transmembrane protein of kidney glomerular podocytes, which appears crucially important for the maintenance of the glomerular filtration barrier. According to its predicted structure, nephrin has additional roles in cell-cell adhesion and/or signal transduction. We have previously cloned the rat homologue of nephrin and described its alternatively spliced transcripts alpha and beta. In this study we examined the alterations in expression and regulation of particularly the major alternatively spliced nephrin-alpha giving rise to a variant lacking the membrane spanning domain in the puromycin nephrosis of the rat. A down-regulation of up to 78% was observed of the full length mRNA after 10 d of PAN treatment. The expression changes of nephrin-alpha followed closely the expression of the full length mRNA. Interestingly, we also found nephrin protein in urine at the peak proteinuria samples of this model. These results suggest that soluble nephrin variants may be important markers for proteinuric diseases.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID