Bartter's syndrome: a unifying hypothesis

The most proximate defect responsible for the pathogenesis of Bartter's syndrome remains uncertain. Although an abnormality in chloride reabsorption in the thick ascending limb of Henle has been postulated, renal clearance studies performed during oral water loading failed to disclose a reduction in fractional chloride reabsorption. We alternatively postulate that the underlying abnormality may reside in a generalized increase in cell sodium permeability. Elevated levels of cell sodium may secondarily stimulate Na-K-ATPase activity. In the cells of the distal nephron, stimulated Na-K-ATPase would lead to enhanced potassium secretion into the tubular fluid producing the characteristic potassium depletion. In addition, increased cell sodium influx may stimulate a sodium-calcium exchanger. If this process exists in vascular smooth muscle, it may result in reduction of cytosolic calcium activity. This effect and/or chronic potassium depletion may mediate the reduced vascular reactivity characteristic of this syndrome.     

Warren K. Sinclair keynote address: contemporary issues in risk-informed decision making on the disposition of radioactive waste

A consistent and transparent risk-informed approach to managing nuclear waste is plagued with different regulators, different rules and regulations for different waste types, different compliance requirements, and indecisions about probabilistic vs. deterministic models. Low-activity waste management is particularly void of a path forward with respect to being risk-informed. Risk assessment is not referenced in the statutes on low-activity waste even though both the U.S. Environmental Protection Agency and U.S. Nuclear Regulatory Commission (U.S. NRC) have policies to apply consistent risk management approaches to all of their programs. The U.S. NRC has developed guidance on the preparation of probabilistic performance assessments for low-activity waste facilities, but there have been no serious takers and a lack of initiative on the part of licensees. Thus, little to no experience exists on risk-informing low-activity waste. The missed opportunities include establishing a risk basis that would allow for simpler, safer, and much less costly alternatives for low-activity waste disposal while enabling society to have the full benefit of radiation technologies. There is hope that congressional action or regulatory rule making will address some of these issues with the result being the adoption of a more general and unified approach to risk-informed regulation of all types of waste. Just as much of the initiative for risk-informed nuclear power came from industry, it must also be the case for nuclear waste. A start would be the adoption of a basic framework of risk assessment in waste management applicable to all types of waste--radioactive and nonradioactive. The "set of triplets" risk assessment framework that is applicable to any kind of risk is an established alternative. It is believed that such a framework with the support of a regulatory structure made compatible through appropriate rulemaking or congressional action, and the experience of the probabilistic performance assessments for the Waste Isolation Pilot Plant and the proposed Yucca Mountain high-level waste repository, could result in the right path forward for the regulation and management of low-activity waste.     

Laser Doppler flowmetry detection of endothelial dysfunction in end-stage renal disease patients: correlation with cardiovascular risk

Prediction of cardiovascular (CV) complications represents the Achilles' heel of end-stage renal disease. Surrogate markers of endothelial dysfunction have been advocated as predictors of CV risk in this cohort of patients. We have recently adapted a noninvasive laser Doppler flowmetry (LDF) functional testing of endothelium-dependent microvascular reactivity and demonstrated that end-stage renal disease patients are characterized by profound alterations in thermal hyperemic responsiveness. We hypothesized that such functional assessment of the cutaneous microcirculation may offer a valid, noninvasive test of the severity of endothelial dysfunction and CV risk. To test this hypothesis, we performed a cross-sectional study, in which we compared LDF measurements to conventional risk factors, and performed a pilot longitudinal study. LDF studies were performed in 70 patients and 33 controls. Framingham and Cardiorisk scores were near equivalent for low-risk patients, but more divergent as risk increased. C reactive protein (CRP) levels and LDF parameters (amplitude of thermal hyperemia (TH), area under the curve of TH) showed significant abnormality in high-risk vs low-risk patients calculated using either Framingham or Cardiorisk scores. Patients who had abnormal LDF parameters showed increased CV mortality, however, had similar risk assessments (Framingham, Cardiorisk, CRP, and homocysteine) to those with unimpaired LDF tracings. In conclusion, LDF parameters of microvascular reactivity offer a sensitive characterization of endothelial dysfunction, which may improve CV risk assessment through incorporation into the Framingham or Cardiorisk algorithm.     

A unified approach to polyene macrolides: synthesis of candidin and nystatin polyols

Polyene macrolide antibiotics are naturally occurring antifungal agents. Members of this class include amphotericin B, which has been used widely to treat systemic fungal infections. A general synthetic strategy has been devised to prepare polyol chains associated with the polyene macrolides. Cyanohydrin acetonide alkylations were used to assemble the carbon skeleton, and a simple modification of the strategy allowed an advanced intermediate to be converted to either the candidin polyol or the nystatin polyol. The candidin polyol was further elaborated to a protected candidin aglycone. This strategy will be applicable to other members of the polyene macrolide natural products.