Our current health care system is failing to meet the needs of our population, particularly with regard to chronic illness and post-acute and long-term care (PA-LTC). Despite widespread dissatisfaction, major reforms are not in sight.

The ESRD program provides medical care to a diverse and medically complex patient population. The care for the ESRD patient population has become increasingly benchmarked with process of care measures. These measures include dialysis adequacy, anemia, nutrition, and vascular access outcomes. These process-related dialysis measures may not improve the care of the individual patient as care relates to the individual's goals and values. There is also evidence that these process measures may not be causally related to quality of life, hospitalization, and survival. The adoption of patient-reported outcomes may shift the balance toward more patient-centered care. However, the extent to which mandated measures of health-related quality of life and patient satisfaction result in improved outcomes remains unclear.

Gene-background interaction is a commonly observed phenomenon in many species, but the molecular mechanisms of such an interaction is less well understood. Here we report the cloning of a maize mutant gene and its modifier. A recessive mutant with a virescent yellow-like (vyl) phenotype was identified in an ethyl methanesulfonate-mutagenized population derived from the maize inbred line B73. Homozygous mutant maize plants exhibited a yellow leaf phenotype after emergence but gradually recovered and became indistinguishable from wild-type plants after approximately 2 weeks. Taking the positional cloning approach, the Chr.9_ClpP5 gene, one of the proteolytic subunits of the chloroplast Clp protease complex, was identified and validated as the candidate gene for vyl. When introgressed by backcross into the maize inbred line PH09B, the mutant phenotype of vyl lasted much longer in the greenhouse and was lethal in the field, implying the presence of a modifier(s) for vyl. A major modifier locus was identified on chromosome 1, and a paralogous ClpP5 gene was isolated and confirmed as the candidate for the vyl-modifier. Expression of Chr.1_ClpP5 is induced significantly in B73 by the vyl mutation, while the expression of Chr.1_ClpP5 in PH09B is not responsive to the vyl mutation. Moreover, expression and sequence analysis suggests that the PH09B Chr.1_ClpP5 allele is functionally weaker than the B73 allele. We propose that functional redundancy between duplicated paralogous genes is the molecular mechanism for the interaction between vyl and its modifier.

Dialysis should not be presumed to be the treatment of choice for all elderly chronic kidney disease stage 5 patients. Nondialysis active medical management, as an alternative to dialysis or palliative care, is a reasonable alternative in select cases. Early referral of CKD 5 elderly patients may lead to early initiation of dialysis, which may not be advantageous; it also provides an opportunity to institute active management as a treatment alternative. The informed decision to proceed with dialysis must involve both an assessment of evidence-based outcomes applicable to the patient, and allowance of patient preference. Prognostic tools are increasingly sought to aid in decision-making for elderly CKD 5 patients. Chronological age alone is not a sufficient predictor of benefit from dialysis treatments, according to observational studies and limited clinical trial data. The survival advantage of dialysis appears to be lost in patients with high levels of comorbidity. Establishing patient preference is an imperfect process, and many patients appear to regret their decision to undergo dialysis. With active medical management, efforts shift from prolonging life to emphasis on symptom control, dietary and medical treatment, and quality of life. Patient survival time can be remarkably long.

Both in the United States and many regions of the world, chronic kidney disease and end-stage renal disease (ESRD) in patients with diabetes mellitus have reached epidemic proportions in recent years. The large prevalent diabetic ESRD population in the US involves remarkable risk in African Americans and an increasing population of elderly diabetic patients, including many octogenarians. In the US and globally, over 90% of diabetic ESRD patients have type 2 diabetes. The multinational epidemic of diabetic ESRD has been linked to increases in the prevalence of diabetes in many populations, related to obesity, ageing, and physical inactivity. It is anticipated that the worldwide prevalence of diabetes over the next 20 years will reach a level twice that of the year 2000. The excessive morbidity and mortality of the diabetic ESRD population are well documented. However, the growth in incidence and prevalence rates for diabetic ESRD has remained somewhat stable in the US in recent years, and new data suggest that the incidence of ESRD expressed per diabetic population may finally be declining, suggesting that proven therapies are making "progress on progression.".

Vascular obstructive causes must be considered in chronic renal failure with no obvious cause. We present the case of a 74-year-old woman with smoldering renal failure who undergoes a renal biopsy that did not undercover a cause. As her symptoms persisted and renal function worsened, her nephrologist proposed magnetic resonance angiography with gadolinium and prophylactic initiation of hemodialysis. Imaging uncovered an occlusive aortic mass, which was removed surgically with improvement in renal function. The case discusses the nature of the mass and the need to weigh the risks and benefits of MR imaging with gadolinium and initiation of hemodialysis against the risk of nephrogenic systemic fibrosis.

Cav2.2 channels play a critical role in pain signaling by controlling synaptic transmission between dorsal root ganglion neurons and dorsal horn neurons. The Cav2.2-selective peptide blocker ziconotide (Prialt (R), Elan Pharmaceuticals, Dublin, Ireland) has proven efficacious in pain relief, but has a poor therapeutic index and requires intrathecal administration. This has provided impetus for finding an orally active, state-dependent Cav2.2 inhibitor with an improved safety profile. Members of the Cav2 subfamily of calcium channels are the main contributors to central and peripheral synaptic transmission, but the pharmacological effects of blocking each subtype is not yet defined. Here we describe a high-throughput fluorescent assay using a fluorometric imaging plate reader (FLIPR (TM) [Molecular Devices, Sunnyvale, CA]) designed to quickly evaluate the state dependence and selectivity of inhibitors across the Cav2 subfamily. Stable cell lines expressing functional Cav2 channels (Ca-V alpha, beta(3), and alpha(2)delta subunits) were co-transfected with an inward rectifier (Kir2.3) so that membrane potential, and therefore channel state, could be controlled by external potassium concentration. Following cell incubation in drug with varying concentrations of potassium, a high potassium trigger was added to elicit calcium influx through available, unblocked channels. State-dependent inhibitors that preferentially bind to channels in the open or inactivated state can be identified by their increased potency at higher potassium concentrations, where cells are depolarized and channels are biased towards these states. Although the Cav2 channel subtypes differ in their voltage dependence of inactivation, by adjusting pre-trigger potassium concentrations, the degree of steady-state inactivation can be more closely matched across Cav2 subtypes to assess molecular selectivity.

Plant oil is an important renewable resource for biodiesel production and for dietary consumption by humans and livestock. Through genetic mapping of the oil trait in plants, studies have reported multiple quantitative trait loci (QTLs) with small effects, but the molecular basis of oil QTLs remains largely unknown 1 , 2 , 3 , 4 , 5 . Here we show that a high-oil QTL ( qHO6 ) affecting maize seed oil and oleic-acid contents encodes an acyl-CoA:diacylglycerol acyltransferase (DGAT1-2), which catalyzes the final step of oil synthesis. We further show that a phenylalanine insertion in DGAT1-2 at position 469 (F469) is responsible for the increased oil and oleic-acid contents. The DGAT1-2 allele with F469 is ancestral, whereas the allele without F469 is a more recent mutant selected by domestication or breeding. Ectopic expression of the high-oil DGAT1-2 allele increases oil and oleic-acid contents by up to 41% and 107%, respectively. This work provides insights into the molecular basis of natural variation of oil and oleic-acid contents in plants and highlights DGAT as a promising target for increasing oil and oleic-acid contents in other crops.

Background/Aims: Because the relation between glycemic control and clinical outcomes found in the general diabetic population has not been established in diabetic hemodialysis patients, we evaluated the association between glycemic control and hospitalization risk. Methods: We performed a primary retrospective data analysis on 23,829 hemodialysis patients with diabetes mellitus. Hemoglobin A1c at baseline and hospitalization events over the subsequent 12 months were analyzed and logistic regression models constructed for unadjusted, case mix-adjusted and case mix plus lab- adjusted data. Models were also constructed for cardiovascular, vascular access and sepsis hospitalizations. Results: Eighty percent had type 2 DM, 5% type 1 and 14% not specified. The groups had similar mean HbA1c levels, 6.8 ± 1.6%. Among all patients, the mean HbA1c values were >7% in 35%. The odds ratio of hospitalizations grouped by baseline HbA1c was significant at extremes of <5% and >11%. Similar relationships were evident for the subset of type 2 DM and in the analysis for hospitalizations due to sepsis. Conclusion: Extremely high and low HbA1c values are associated with hospitalization risk in diabetic hemodialysis patients. Prospective studies are needed to determine whether meeting recommended HbA1c targets might improve outcomes without posing additional risks in this population.

Background: Renal insufficiency is a well-described risk factor for perioperative morbidity and shortened survival after major vascular procedures. Due to the potential inaccuracy of serum creatinine levels alone in measuring kidney function, our aim was to determine whether estimated creatinine clearance more consistently predicted long-term survival. Methods: A retrospective review of one institution’s vascular registry was performed. Logistic regression analysis was conducted to determine independent predictors of 1-, 2- and 3-year postoperative mortality. Creatinine clearance was estimated as [140 – age (years)] × weight (kg)/72 × serum creatinine (mg/dl), multiplied by 0.85 for women. Results: A total of 252 consecutive patients underwent infrainguinal bypass procedures between August 1999 and May 2000. Demographics included average age 68 years, 65% male, 74% diabetic, 12% dialysis-dependent, 23% history of congestive heart failure, 12% history of stroke and 20% serum creatinine >2 mg/dl. One-year mortality was 16% (n = 40), 2-year mortality was 25% (n = 64), and 3-year mortality was 35% (n = 88). There was no difference in serum creatinine values between survivors and non-survivors at 1 year (1.8 vs. 1.9, p = 0.80), 2 years (1.8 vs. 2.0, p = 0.62) or 3 years (1.8 vs. 2.0, p = 0.24), and creatinine >2 mg/dl did not predict long-term adverse outcomes. In contrast, reduced creatinine clearance (≤60 ml/min) was an independent predictor of mortality regardless of dialysis status (1 year: OR = 2.53, p = 0.014; 2 years: OR = 2.46, p = 0.004; 3 years: OR = 2.45, p = 0.001), and creatinine clearance was higher for survivors versus non-survivors at all 3 time points (1 year: 70.2 vs. 49.5, p = 0.003; 2 years: 72.3 vs. 51.2, p < 0.0001; 3 years: 74.7 vs. 52.6, p < 0.0001). Other independent predictors of mortality included a history of stroke (1 year: OR = 3.28, p = 0.008; 2 years: OR = 2.55, p = 0.025; 3 years: OR = 2.35, p = 0.038) and congestive heart failure (1 year: OR = 2.86, p = 0.006; 2 years: OR = 2.54, p = 0.005; 3 years: OR = 2.13, p = 0.017). Conclusions: Independent of dialysis status, a decreased creatinine clearance, but not elevated serum creatinine alone, is an independent predictor of mortality after lower extremity arterial reconstruction. Determination of creatinine clearance should replace serum creatinine in the preoperative risk evaluations of patients undergoing major vascular surgical procedures.