To study the molecular mechanisms controlling guanylin expression, we have cloned the mouse guanylin gene, including 2.7 kb of upstream sequence. We show that the first 133 base pairs (bp) of the upstream guanylin promoter are sufficient to drive near maximal (6-fold over basal) luciferase reporter gene expression in Caco-2 intestinal cells; at least 300 bp of upstream promoter are required for reporter gene expression in HT-29 intestinal cell lines. Using electromobility shift assays, we demonstrate that nuclear proteins bind to the hepatocyte nuclear factor-1 (HNF-1) consensus sequence in the guanylin promoter. The HNF-1 consensus sequence, located in the immediate 5′ flanking region, is required for transcriptional activation of the guanylin gene in both intestinal cell lines. Mutagenesis of the HNF-1 consensus sequence abolishes transcriptional activation of guanylin promoter-luciferase reporter gene constructs. Cotransfection of these constructs with HNF-1α augments transcriptional initiation of the reporter gene. In contrast, HNF-1β has no significant effect on transcription of the reporter gene. These experiments demonstrate that HNF-1α is an important regulatory element in the transcriptional activation of guanylin.
Sodium is usually included in hospitals' critical values lists; however, the values at which sodium is considered to be life threatening (critical) vary among hospitals. Studies of outcomes associated with hyponatremia and hypernatremia in pediatric patients have not been published. We performed a retrospective chart review of sodium values of <124 mmol/L and >155 mmol/L that occurred during a 6-month period. Univariate and multivariate analyses for mortality risk were performed with the different variables. A total of 702 (1.32%) sodium tests fell in the study reference range, with 166 being <124 mmol/L and 536 being >155 mmol/L. Although not statistically significant, mortality was higher (38.5%) in patients with sodium values ≤ 120 mmol/L than in those with values ≥ 170 mmol/L (25%) or in patients with other values (<14%). Underlying conditions prevented assessment of morbidity associated with hyponatremia or hypernatremia. Treatment was instituted within 4 hours in 80% of cases (50% within 1 hour). Multivariate analysis showed increased risk of death for hyponatremic patients if they were premature or had heart abnormalities, while for hypernatremic patients the risk increased when other critical values were present. In conclusion, sodium levels of ≤ 120 mmol/L and ≥ 170 mmol/L have increased mortality in children; however, the risk of death is not statistically different when compared to risk in patients with milder hyponatremia and hypernatremia. Risk factors for death in hyponatremic and hypernatremic patients may primarily reflect the severity of the underlying conditions present in these children, such as prematurity and heart abnormalities, rather than the sodium derangement.
Catheter-free prolonged esophageal pH monitoring is feasible in children older than 6 years of age. A lack of consistent reproducibility in sequential 24 hour recordings with this technique concurs with findings using the conventional catheter methodologies. The catheter-free system is often associated with discomfort during the study, but these symptoms were generally well tolerated.
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