Thanh Q Le

Intestinal and Hepatic Cholesterogenesis in Hypercholesterolemic Dyslipidemia of Experimental Diabetes in Dogs

We previously reported that dog diabetes results in hypercholesterolemia and the accumulation of a high-density lipoprotein (HDL) subclass, HDL1. Hypercholesterolemic diabetic rodents exhibit hyperphagia, intestinal hypertrophy, and increased intestinal cholesterol synthesis and absorption; intestinal 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity is increased, whereas hepatic activity is unchanged or reduced. To determine whether similar mechanisms operate in the hypercholesterolemic diabetic dog, we measured hepatic and intestinal cholesterologenesis. Streptozocin-alloxan–induced diabetic dogs allowed access to food ad libitum were hyperphagic and hypercholesterolemic (10.1 vs. 4.47 mM) but normotriglyceridemic. Plasma HDL1 concentrations were markedly increased. Differences in renal and hepatic function were not statistically significant, except serum alkaline phosphatase, which was elevated 4-fold (P = 0.0003). Urinary mevalonate, an index of whole-body cholesterol synthesis, was increased 6-fold. Intestinal and hepatic weights were both increased, and direct measurements showed crypt and villus thickening. The activity of HMG CoA reductase per gram organ weight was increased 1.7-fold in liver and 2.1-fold in intestine. Calculated whole-organ activity in intestine was nearly twice that in liver. These observations provide strong evidence that intestinal cholesterogenesis is involved in the pathogenesis of hypercholesterolemia in dog diabetes and support the conclusion that increased cholesterol synthesis plays a role in the hypercholesterolemia of diabetes.

Plasma apolipoprotein E, high density lipoprotein1 (HDL1) and urinary mevalonate excretion in pancreatectomized diabetic dogs: effects of insulin and lovastatin.

Hypercholesterolemia and increased concentrations of an apolipoprotein E (apoE)-containing HDL subclass, high density lipoprotein1 (HDL1) have been observed in streptozocin-alloxan diabetic dogs consuming normal amounts of dietary cholesterol. The aim of this study was to characterize the response of HDL1 and its targeting ligand, apoE, to insulin and HMG-CoA reductase inhibitor treatment in pancreatectomized diabetic dogs. Following induction of diabetes, plasma total cholesterol, HDL1, and apoE concentrations were all increased. Urinary mevalonate excretion, an index of cholesterol synthesis in humans, was 6-fold that of nondiabetic controls. Lipoprotein fractionation by Pevikon block electrophoresis and gel filtration chromatography showed that the increased cholesterol and apoE were associated with alpha 2-migrating particles corresponding to HDL1. Insulin treatment, resulting in near normal fasting blood glucose concentrations in the group as a whole (average 5.1 mM, 92 mg/dl), led to variable reductions in apoE, total plasma cholesterol, and HDL1. Uncorrected dyslipidemia during intensified insulin treatment appeared to be related to failure to achieve euglycemia. Despite unremitting hyperglycemia, treatment with lovastatin resulted in pronounced decreases in plasma cholesterol, HDL1 and apoE to concentrations below those observed in nondiabetic animals. Mevalonate excretion also fell, but remained twice normal. Thus neither modality corrected all of the abnormalities in canine diabetic dyslipidemia. Since apoE-containing HDL1 may mediate cholesterol traffic between the periphery and the liver (reverse cholesterol transport), the present observations suggest that increased cholesterol synthesis is accompanied by parallel abnormalities in cholesterol flux through the reverse transport pathway in the canine model.

Safety Evaluation of Geometric Design Criteria for Spacing of Entrance-Exit Ramp Sequence and Use of Auxiliary Lanes

Geometric design decisions regarding interchange and ramp spacing on freeways have traditionally taken a nominal approach to safety. This approach oversimplifies driver behavior and complex interactions between roadway geometrics, traffic operations, and safety and tends to promote a one-size-fits-all approach to evaluating design alternatives. The objective of this paper was to quantify the relationship between ramp spacing and freeway safety. Data for this study included freeway geometric features, traffic characteristics, and crash counts for 404 freeway segments in California and Washington State. A negative binomial regression modeling approach was used to explore the relationship between ramp spacing and safety. Results indicated that expected crash frequency increased as ramp spacing decreased. The expected proportion of crashes resulting in a fatality or injury appeared to decrease as ramp spacing decreased. The presence of an auxiliary lane was associated with a lower expected frequency of crashes for any given ramp spacing; the safety benefits of providing an auxiliary lane diminished as ramp spacing increased. The model results related to ramp spacing and the presence of an auxiliary lane were transformed into crash modification factors and validated through comparisons with an independent research study on weaving areas in Texas. The safety findings were generally consistent with current Green Book design criteria related to ramp spacing and the presence of an auxiliary lane. The ability to quantify the expected impact on safety of ramp spacing associated with new or modified interchanges will assist transportation agencies in making well-informed assessments of the overall benefits, impacts, and costs of freeway access decisions.

Guidelines for Spacing Between Freeway Ramps

Existing geometric design guidance related to interchange ramp spacing in the Texas Roadway Design Manual and AASHTOs Policy on Geometric Design of Highways and Streets is not speed dependent even though intuition indicates that spacing and speed are related. Understanding the relationship between interchange ramp spacing, speed, and freeway operations is important, especially in developing potential design values for higher speeds (e.g., 85 to 100 mph). The objectives of this Texas Department of Transportation project were (a) to investigate relationships between weaving length, speed, and overall vehicle operations for successive ramps on Texas freeways and (b) to propose updates to current guidance on recommended distances between ramps. Several methods were used to assist in developing guidance on ramp spacing lengths. The methods and resources used to generate potential lengths included (a) guidance provided in the Design Manual for Roads and Bridges published by the Highways Agency in England, (b) minimum deceleration and acceleration lengths for freeway conditions, (c) decision sight distance, (d) sign spacing needs, (e) NCHRP Project 3–75 findings, (f) findings from field studies at seven sites in Texas, (g) findings from simulation conducted as part of this research, and (h) safety relationships identified in the literature. Suggested ramp spacings were developed for the entrance–exit and exit–exit ramp scenarios.

Combined Crash Frequency–Crash Severity Evaluation of Geometric Design Decisions: Entrance–Exit Ramp Spacing and Auxiliary Lane Presence

This paper quantified the effects of freeway ramp spacing and auxiliary lane presence on crash frequency and crash severity. Crash frequencies were predicted with a safety performance function, and crash severities were estimated with what was termed a “severity distribution function.” The paper then demonstrated how to combine quantitative knowledge related to the effects of ramp spacing and auxiliary lane presence on both crash frequency and severity into a framework for assessing the overall crash cost for different ramp configurations. Geometric features, traffic characteristics, and crash data were collected for 404 freeway segments in California and Washington State. Negative binomial regression models and multinomial logit regression models were used to estimate the effects of ramp spacing and auxiliary lane presence on expected crash frequencies and crash severities, respectively. Results showed that expected multiple-vehicle crash frequency increased as ramp spacing decreased. Meanwhile, there was a decrease in the proportion of severe crashes (fatal, incapacitating injury) with a decrease in ramp spacing, even though the overall frequency of these severe crashes remained relatively unchanged. Providing an auxiliary lane was expected to decrease crash frequency, although this reduction appeared to be primarily in crashes that were less severe (possible injury and property damage only). The findings appeared to effectively capture the complex relationships between geometric designs and operations and the high sensitivity between speed and crash severity. The paper provided quantitative tools for making informed freeway and interchange design decisions where ramp spacing and auxiliary lanes were considerations.

Safety Evaluation of Turning Movement Restrictions at Stop-Controlled Intersections

This study evaluates the safety effectiveness of physical right-in-right-out (RIRO) operations compared with full turning movements at stop-controlled intersections. Geometric, traffic, and crash d...

Safety Effects of Low-Cost Systemic Safety Improvements at Signalized and Stop-Controlled Intersections

Packages of intersection treatments—including signing, pavement marking, and signal enhancements—were installed at many signalized and stop-controlled intersections in South Carolina. This study evaluated the overall safety-effectiveness of the concurrent implementation of these systemic low-cost treatments as part of the FHWA Evaluations of Low Cost Safety Improvements Pooled Fund. The data set included both urban and rural three-leg and four-leg intersections with two or four lanes on the major road. The study employed an empirical Bayes before-and-after analysis. The aggregate results indicate reductions for all crash types analyzed in this study. For signalized intersections, the crash modification factors (CMFs) are 0.955, 0.893, 0.974, 0.883, and 0.969 for total, fatal and injury, rear-end, right-angle, and nighttime crashes, respectively. The CMFs for fatal and injury and right-angle crashes are statistically significant at the 95% confidence level and the CMF for total crashes is statistically significant at the 90% confidence level. For stop-controlled intersections, the CMFs are 0.917, 0.899, 0.933, 0.941, and 0.853 for total, fatal and injury, rear-end, right-angle, and nighttime crashes, respectively. All CMFs for stop-controlled intersections are statistically significant at the 95% confidence level. An economic analysis shows that systemic, low-cost intersection treatments are cost-effective with conservative benefit–cost ratio estimates of 4.1 for total crashes at signalized intersections and 12.4 for total crashes at stop-controlled intersections.