High-resolution serum proteomic profiling of Alzheimer disease samples reveals disease-specific, carrier-protein-bound mass signatures.

BACKGROUND: Researchers typically search for disease markers using a "targeted" approach in which a hypothesis about the disease mechanism is tested and experimental results either confirm or disprove the involvement of a particular gene or protein in the disease. Recently, there has been interest in developing disease diagnostics based on unbiased quantification of differences in global patterns of protein and peptide masses, typically in blood from individuals with and without disease. We combined a suite of methods and technologies, including novel sample preparation based on carrier-protein capture and biomarker enrichment, high-resolution mass spectrometry, a unique cohort of well-characterized persons with and without Alzheimer disease (AD), and powerful bioinformatic analysis, that add statistical and procedural robustness to biomarker discovery from blood. METHODS: Carrier-protein-bound peptides were isolated from serum samples by affinity chromatography, and peptide mass spectra were acquired by a matrix-assisted laser desorption/ionization (MALDI) orthogonal time-of-flight (O-TOF) mass spectrometer capable of collecting data over a broad mass range (100 to >300,000 Da) in a single acquisition. Discriminatory analysis of mass spectra was used to process and analyze the raw mass spectral data. RESULTS: Coupled with the biomarker enrichment protocol, the high-resolution MALDI O-TOF mass spectra provided informative, reproducible peptide signatures. The raw mass spectra were analyzed and used to build discriminant disease models that were challenged with blinded samples for classification. CONCLUSIONS: Carrier-protein enrichment of disease biomarkers coupled with high-resolution mass spectrometry and discriminant pattern analysis is a powerful technology for diagnostics and population screening. The mass fingerprint model successfully classified blinded AD patient and control samples with high sensitivity and specificity.

Results of a pilot pharmacotherapy quality improvement program using fixed-dose, combination amlodipine/benazepril antihypertensive therapy in a long-term care setting.

BACKGROUND: Hypertension is common in older adults (aged > or =65 years). Treatment frequently requires multiple medications and can be expensive. OBJECTIVE: This study measured the impact of substituting low-dose, fixed-combination therapy using the calcium channel blocker (CCB) amlodipine and the angiotensin-converting enzyme (ACE) inhibitor benazepril for high-dose CCB monotherapy or dual therapy with a CCB and an ACE inhibitor on antihypertensive drug costs, the incidence of adverse events, and blood-pressure control. METHODS: A multicenter, pilot pharmacotherapy quality improvement program was undertaken in a long-term care facility setting. Consultant pharmacists reviewed pharmacy records and medical charts from long-term care facilities, identifying older patients with a diagnosis of hypertension who either took CCB concomitantly with an ACE inhibitor or experienced adverse events on high-dose CCB therapy. Eligible patients were identified and their physicians contacted regarding switching them to fixed-dose combination therapy. RESULTS: A total of 51 patients at 17 facilities were switched to fixed-dose amlodipine/benazepril combination therapy; 94.1% were women and 5.9% were men (mean age, 85.1 years; range, 64-99 years). The mean number of comorbidities was 1.6. During the subsequent 2 months, mean blood pressure remained at levels similar to those at baseline. The number of patients reporting at least 1 drug-related adverse event decreased by 81.8% (P < 0.05), and the incidence of edema decreased by 75.0%. The mean per-patient cost of antihypertensive drugs decreased by 33.1% (P < 0.001), a mean per-patient savings of 19.21 US dollars per month. CONCLUSION: In patients aged > or =65 years with hypertension in long-term care facilities, a change from high-dose CCB monotherapy or CCB/ACE-inhibitor dual therapy to fixed-dose combination amlodipine/benazepril therapy significantly reduced drug costs and the incidence of adverse events and maintained blood-pressure control.

Development of a microparticle-based on-site immunoassay for the detection of atrazine in soil and water samples.

Atrazine is widely used as a herbicide in agriculture and has been identified as a major groundwater contaminant in the US. Because of the possible hazard associated with its usage, there is a need for an efficient and economic screening method for on-site field testing of atrazine and other s-triazine herbicides in soil and water. We have developed a rapid, on-site test for the detection of atrazine based on the principle of microparticle agglutination inhibition immunoassay. The test detects 50 microg kg(-1) (0.050 ppm) atrazine in soil samples with direct extraction and 1.0 microg L(-1) atrazine in water samples when coupled with solid phase extraction.

Low intraindividual variability of cyclosporin A exposure reduces chronic rejection incidence and health care costs.

The present study applied a receiver operating characteristic (ROC) analysis to assess the role of intraindividual variability of cyclosporin A (CsA) drug exposure in predisposing renal transplant recipients to the occurrence of chronic rejection, as well as to increased health care costs using a resource-based economic analysis. Two hundred and four adult renal transplant recipients were treated with tapering doses of prednisone (Pred) and with a concentration-controlled strategy that selected doses of the olive oil-based formulations of CsA (Sandimmune(R)) that achieved target concentrations based on serial pharmacokinetic profiles. The ROC analysis revealed an inflection point of plots of the coefficient of variation (%CV) of CsA exposure versus the risk of chronic rejection at >/=28.4% for the average concentration (C(av)), i.e., the dosing interval-corrected area under the concentration-time curves, and >/=36% for the trough concentration (C(0)). The incidence of chronic rejection over a period of 5 yr was 24% among the less variable (LV) versus 40% among the variable (V) cohort. The economic analysis revealed that the total mean facility and physician costs per patient were $48,789 versus $60,998, respectively (P < 0.01). The degree of variability displayed by any individual could only be predicted by serial measurements of CsA concentrations, and not by demographic features, laboratory determinations, clinical characteristics, individual or mean values of any observed CsA concentration, or other pharmacokinetic parameters calculated following a single drug exposure. Thus, strategies that reduce intrapatient variability of CsA exposure over time may lead to reductions in chronic allograft loss and in treatment costs.