A Multidisciplinary Consensus for Clinical Care and Research Needs for Sturge-Weber Syndrome.

BACKGROUND: Sturge-Weber syndrome is a neurocutaneous disorder associated with port-wine birthmark, leptomeningeal capillary malformations, and glaucoma. It is associated with an unpredictable clinical course. Because of its rarity and complexity, many physicians are unaware of the disease and its complications. A major focus moving ahead will be to turn knowledge gaps and unmet needs into new research directions. METHODS: On October 1-3, 2017, the Sturge-Weber Foundation assembled clinicians from the Clinical Care Network with patients from the Patient Engagement Network of the Sturge-Weber Foundation to identify our current state of knowledge, knowledge gaps, and unmet needs. RESULTS: One clear unmet need is a need for consensus guidelines on care and surveillance. It was strongly recommended that patients be followed by multidisciplinary clinical teams with life-long follow-up for children and adults to monitor disease progression in the skin, eye, and brain. Standardized neuroimaging modalities at specified time points are needed together with a stronger clinicopathologic understanding. Uniform tissue banking and clinical data acquisition strategies are needed with cross-center, longitudinal studies that will set the stage for new clinical trials. A better understanding of the pathogenic roles of cerebral calcifications and stroke-like symptoms is a clear unmet need with potentially devastating consequences. CONCLUSIONS: Biomarkers capable of predicting disease progression will be needed to advance new therapeutic strategies. Importantly, how to deal with the emotional and psychological effects of Sturge-Weber syndrome and its impact on quality of life is a clear unmet need.

P53 and cellular glucose uptake.

OBJECTIVES: Tumor protein p53 is a transcription factor involved with cellular responses to stressors including limited glucose availability. We hypothesized that modulating p53 levels would affect cellular glucose uptake. METHODS AND RESULTS: Transfecting cultured primary mouse hepatocytes with p53 siRNA suppressed p53 mRNA expression >90%. Control hepatocytes (transfected with non-targeting siRNA) increased glucose uptake (2.28 ± 1.02-fold vs basal, p 0.009) in response to 100 nM insulin, but p53 siRNA-treated hepatocytes had a blunted response (0.92 ± 0.11-fold vs basal; between group difference p 0.0012). In adipocytes differentiated from the pre-adipocyte line 3T3-L1, knockdown of p53 had no effect on insulin-stimulated glucose uptake. There were no differences in Glut 1 or Glut 2 expression in the plasma membrane fraction or in the levels of phosphorylated AKT in cell lysates between primary hepatocytes transfected with p53 siRNA or control siRNA. Glycemic responses to insulin tolerance, glucose tolerance, and pyruvate tolerance tests did not differ between p53 knockout and wild type mice. DISCUSSION: Thus, inhibition of p53 has pleiotropic effects, inhibiting glucose uptake in the liver but having no effect on adipocytes. Knockout of p53 has no apparent effect on glucose homeostasis in intact lean mice. An explanation for the association between p53 expression and hepatocyte glucose uptake remains to be elucidated.

Dose-dependent effects of prenatal ethanol exposure on synaptic plasticity and learning in mature offspring.

BACKGROUND: We have observed profound deficits in hippocampal synaptic plasticity and one-trial learning in offspring whose mothers drank moderate quantities of ethanol during pregnancy. In the present study, we examined the question of whether lower maternal blood ethanol concentrations (BECs) could produce functional deficits in offspring. METHODS: Rat dams consumed either a 2%, 3%, or 5% ethanol liquid diet throughout gestation. Three other groups of dams were pair-fed a 0% ethanol liquid diet, and a seventh group consumed lab chow ad libitum. Adult offspring from each diet group were assigned either to studies of evoked [3H]-D-aspartate (D-ASP) release from hippocampal slices or spatial learning studies using the Morris Water Task. RESULTS: Consumption of the 2%, 3%, and 5% ethanol liquid diets produced mean peak maternal BECs of 7, 30 and 83 mg/dL, respectively. Consumption of these ethanol diets had no effect on offspring birthweight, litter size or neonatal mortality. Likewise, evoked D-ASP release from hippocampal slices and performance on a standard version of the Morris Water Task were not affected by prenatal ethanol exposure. By contrast, activity-dependent potentiation of evoked D-ASP release from slices and one-trial learning on a "moving platform" version of the Morris Water Task were markedly reduced in offspring whose mothers consumed the 5% ethanol liquid diet. Intermediate deficits in these two parameters were observed in offspring from the 3% ethanol diet group, whereas offspring from the 2% ethanol diet group were not statistically different than controls. CONCLUSIONS: We conclude that the threshold for eliciting subtle, yet significant learning deficits in offspring prenatally exposed to ethanol is less than 30 mg/dL. This BEC is roughly equivalent to drinking 1 to 1.5 ounces of ethanol per day.