Modifications of the ABCD2 score do not improve the risk stratification of transient ischemic attack patients.

BACKGROUND: Modifications to the age, blood pressure, clinical symptoms, duration of symptoms, and diabetes (ABCD2) score, which incorporate history of hypertension and acute hyperglycemia in addition to acute blood pressure (BP) elevation and history of diabetes, have been proposed to increase the predictive value of the score. In addition, the timing of acute BP measurement may be important in the emergency department (ED) setting, given the phenomenon of "ED triage hypertension". METHODS: The standard ABCD2 score was compared to modified scores incorporating various combinations of acute BP elevation or hyperglycemia, history of hypertension or diabetes, and subsequent versus initial ED BP measurements. The number of patients reclassified into an alternate risk category (low/moderate/high) with different schemes was determined. Predictive value using the composite outcome of stroke, death, or high-risk transient ischemic attack mechanism was assessed using c statistics. RESULTS: Modified ABCD2 scores resulted in few patients shifting risk categories (between 2% and 10% for six alternate schemes), and did not improve the performance of the ABCD2 score (c-statistics, 0.61-0.65, compared to 0.63 for the standard score). ED triage hypertension was frequent (mean systolic blood pressure [SBP]/diastolic blood pressure [DBP] decrease of 8/9 mm Hg on subsequent measurement; P < .001), but the use of second BP did not reclassify many patients (10%) nor did it improve score performance (c-statistic, 0.61). CONCLUSIONS: Modifications of the ABCD2 score changed the risk category for few patients and did not improve the overall predictive value of the score.

Noninflammatory cerebral vasculopathy associated with recurrent ischemic strokes.

Recurrent ischemic strokes often have uncommon causes in young adults. Vascular abnormalities may be considered as a possible etiology. We report a 36-year-old man who experienced recurrent cryptogenic ischemic strokes despite medical therapy. Conventional cerebral angiography was unrevealing. Subsequent brain biopsy revealed a distinctive histopathological pattern of abnormal perivascular collagen deposition without inflammation. Recurrent cryptogenic strokes may have novel etiologies, and brain biopsy should be considered when standard diagnostic tests fail.

Positive feedback regulates switching of phosphate transporters in S. cerevisiae.

The regulation of transporters by nutrient-responsive signaling pathways allows cells to tailor nutrient uptake to environmental conditions. We investigated the role of feedback generated by transporter regulation in the budding yeast phosphate-responsive signal transduction (PHO) pathway. Cells starved for phosphate activate feedback loops that regulate high- and low-affinity phosphate transport. We determined that positive feedback is generated by PHO pathway-dependent upregulation of Spl2, a negative regulator of low-affinity phosphate uptake. The interplay of positive and negative feedback loops leads to bistability in phosphate transporter usage--individual cells express predominantly either low- or high-affinity transporters, both of which can yield similar phosphate uptake capacity. Cells lacking the high-affinity transporter, and associated negative feedback, exhibit phenotypes that arise from hysteresis due to unopposed positive feedback. In wild-type cells, population heterogeneity generated by feedback loops may provide a strategy for anticipating changes in environmental phosphate levels.

Noise in gene expression: origins, consequences, and control.

Genetically identical cells and organisms exhibit remarkable diversity even when they have identical histories of environmental exposure. Noise, or variation, in the process of gene expression may contribute to this phenotypic variability. Recent studies suggest that this noise has multiple sources, including the stochastic or inherently random nature of the biochemical reactions of gene expression. In this review, we summarize noise terminology and comment on recent investigations into the sources, consequences, and control of noise in gene expression.

Control of stochasticity in eukaryotic gene expression.

Noise, or random fluctuations, in gene expression may produce variability in cellular behavior. To measure the noise intrinsic to eukaryotic gene expression, we quantified the differences in expression of two alleles in a diploid cell. We found that such noise is gene-specific and not dependent on the regulatory pathway or absolute rate of expression. We propose a model in which the balance between promoter activation and transcription influences the variability in messenger RNA levels. To confirm the predictions of our model, we identified both cis- and trans-acting mutations that alter the noise of gene expression. These mutations suggest that noise is an evolvable trait that can be optimized to balance fidelity and diversity in eukaryotic gene expression.