The Clinical Utility of a Precision Medicine Blood Test Incorporating Age, Sex, and Gene Expression for Evaluating Women with Stable Symptoms Suggestive of Obstructive Coronary Artery Disease: Analysis from the PRESET Registry.

Background: Evaluating women with symptoms suggestive of coronary artery disease (CAD) remains challenging. A blood-based precision medicine test yielding an age/sex/gene expression score (ASGES) has shown clinical validity in the diagnosis of obstructive CAD. We assessed the effect of the ASGES on the management of women with suspected obstructive CAD in a community-based registry. Materials and Methods: The prospective PRESET (A Registry to Evaluate Patterns of Care Associated with the Use of Corus® CAD in Real World Clinical Care Settings) Registry (NCT01677156) enrolled 566 patients presenting with symptoms suggestive of stable obstructive CAD from 21 United States primary care practices from 2012 to 2014. Demographics, clinical characteristics, and referrals to cardiology or further functional and/or anatomical cardiac studies after ASGES testing were collected for this subgroup analysis of women from the PRESET Registry. Patients were followed for 1-year post-ASGES testing. Results: This study cohort included 288 women with a median age 57 years. The median body mass index was 29.2, with hyperlipidemia and hypertension present in 48% and 43% of patients, respectively. Median ASGES was 8.5 (range 1-40), with 218 (76%) patients having low (≤15) ASGES. Clinicians referred 9% (20/218) low ASGES versus 44% (31/70) elevated ASGES women for further cardiac evaluation (odds ratio 0.14, p < 0.0001, adjusted for patient demographics and clinical covariates). Across the score range, higher ASGES were associated with a higher likelihood of posttest cardiac referral. At 1-year follow-up, low ASGES women experienced fewer major adverse cardiac events than elevated ASGES women (1.3% vs. 4.2% respectively, p = 0.16). Conclusions: Incorporation of ASGES into the diagnostic workup demonstrated clinical utility by helping clinicians identify women less likely to benefit from further cardiac evaluation

Efficacy of Mammographic Evaluation of Breast Cancer in Women Less Than 40 Years of Age: Experience from a Single Medical Center in Taiwan

Background/PurposeMammography is the standard imaging modality for breast cancer diagnosis. However, the value of mammographic diagnosis in breast cancer patients aged less than 40 years old has not been well assessed. The goal of our study was to determine the diagnostic efficacy of mammography for the detection of breast cancer in women under 40 years of age in a single medical center in Taiwan.MethodsOf 1766 women diagnosed with breast cancer in one medical center between 1999 and 2005, 227 (12.9%) who were younger than 40 years of age were enrolled, and 105 of these 227 patients had pre-biopsy mammograms available for analysis. The sensitivities for mammography at first (prospective) and second (retrospective) readings and for corresponding ultrasound were calculated. The distribution of different breast composition between the mammographic true-positive (TP) and false-negative (FN) lesions at the first and second readings was analyzed.ResultsOf the 105 patients, 104 presented with a palpable mass and the other one was asymptomatic. There were 109 pathologically proven breast cancers from the 105 patients; 92 of 109 cancerous lesions were detected at the first mammographic reading (sensitivity 84.4%), and the most common mammographic sign was microcalcifications (40.2%). The second reading detected seven additional cancers (99 of 109 lesions; sensitivity 90.8%). There was no significant difference between mammographic TP and FN lesions for the different breast composition on first and second readings. Ninety patients also had ultrasound available for correlation with 94 cancers diagnosed from them. The diagnostic sensitivity of ultrasound was 94.7% (89 of 94 lesions).ConclusionMammography has an acceptable sensitivity for the detection of breast cancer in women aged less than 40 years, regardless of different breast composition. Breast ultrasound can offer a higher sensitivity for such a population

Identification of the histidine ligands to the binuclear metal center of phosphotriesterase by site-directed mutagenesis

ABSTRACT: In order to identify which of the seven histidines in phosphotriesterase participate a t the active site/binuclear metal center of the enzyme, site-directed mutagenesis has been employed to change, individually, each of the seven histidine residues to asparagine. In addition, the gene for the wild-type enzyme has been subcloned without its leader sequence behind a modified ribosomal binding site, leading to a 5-fold increase in protein expression. The seven mutants The bacterial phosphotriesterase from Pseudomonas diminuta is a zinc metalloenzyme, which catalyzes the hydrolysis of a variety of organophosphate triesters, including the insecticide paraoxon: The reaction proceeds via an S~2-like mechanism and likely involves an amino acid residue acting as a general base to assist in the deprotonation of an activated water molecule, which then directly attacks the substrate 845-9452. with a variety of different metals. Replacement of the naturally occurring zinc(I1) metal with other divalent cations, such as cadmium(II), cobalt(II), manganese(II), or nickel(II), apparently does not alter the conformation of the protein, since the specific activities of the various metalsubstituted phosphotriesterase derivatives remain the same or are increased significantly over that of the native zinc enzyme High-resolution '13Cd nuclear magnetic resonance (NMR) spectra of the 113Cd-substituted phosphotriesterase show two cadmium resonances at 212 (Ma site) and 116 ppm (MB site) downfield from Cd(C10&, indicating that the chemical environments around the two metal ions are somewhat different from each other Electron paramagnetic resonance spectroscopy of the manganese-substituted phosphotriesterase indicates that the two Mn(I1) ions are present as an antiferromagnetically exchange-coupled binuclear metal complex (Chae et al., 1993). This requires the two metal sites to be in close proximity and 0006-2960/94/0433-4265$04.50/0 I

Significant association of hematinic deficiencies and high blood homocysteine levels with burning mouth syndrome

Background/PurposeBurning mouth syndrome (BMS) is characterized by a burning sensation of the oral mucosa in the absence of clinically apparent mucosal alterations. In this study, we evaluated whether there was an intimate association of the deficiency of hemoglobin (Hb), iron, vitamin B12, or folic acid; high blood homocysteine level; and serum gastric parietal cell antibody (GPCA) positivity with BMS.MethodsBlood Hb, iron, vitamin B12, folic acid, and homocysteine concentrations and the serum GPCA level were measured in 399 BMS patients and compared with the corresponding levels in 399 age- and sex-matched healthy control individuals.ResultsWe found that 89 (22.3%), 81 (20.3%), 10 (2.5%), and six (1.5%) BMS patients had deficiencies of Hb (men: <13 g/dL, women: <12 g/dL), iron (<60 μg/dL), vitamin B12 (<200 pg/mL), and folic acid (<4 ng/mL), respectively. Moreover, 89 (22.3%) BMS patients had abnormally high blood homocysteine level and 53 (13.3%) had serum GPCA positivity. BMS patients had a significantly higher frequency of Hb, iron, or vitamin B12 deficiency; of abnormally elevated blood homocysteine level; or of serum GPCA positivity than the healthy control group (all p < 0.001 except for vitamin B12 deficiency, for which p = 0.004). However, no significant difference in frequency of folic acid deficiency (p = 0.129) was found between BMS patients and healthy control individuals.ConclusionWe conclude that there is a significant association of deficiency of Hb, iron, and vitamin B12; abnormally high blood homocysteine level; and serum GPCA positivity with BMS

Plasma metabolomic profiles predict near-term death among individuals with lower extremity peripheral arterial disease

BackgroundIndividuals with peripheral arterial disease (PAD) have a nearly two-fold increased risk of all-cause and cardiovascular disease mortality compared to those without PAD. This pilot study determined whether metabolomic profiling can accurately identify patients with PAD who are at increased risk of near-term mortality.MethodsWe completed a case-control study using 1H NMR metabolomic profiling of plasma from 20 decedents with PAD, without critical limb ischemia, who had blood drawn within 8 months prior to death (index blood draw) and within 10 to 28 months prior to death (preindex blood draw). Twenty-one PAD participants who survived more than 30 months after their index blood draw served as a control population.ResultsResults showed distinct metabolomic patterns between preindex decedent, index decedent, and survivor samples. The major chemical signals contributing to the differential pattern (between survivors and decedents) arose from the fatty acyl chain protons of lipoproteins and the choline head group protons of phospholipids. Using the top 40 chemical signals for which the intensity was most distinct between survivor and preindex decedent samples, classification models predicted near-term all-cause death with overall accuracy of 78% (32/41), a sensitivity of 85% (17/20), and a specificity of 71% (15/21). When comparing survivor with index decedent samples, the overall classification accuracy was optimal at 83% (34/41) with a sensitivity of 80% (16/20) and a specificity of 86% (18/21), using as few as the top 10 to 20 chemical signals.ConclusionsOur results suggest that metabolomic profiling of plasma may be useful for identifying PAD patients at increased risk for near-term death. Larger studies using more sensitive metabolomic techniques are needed to identify specific metabolic pathways associated with increased risk of near-term all-cause mortality among PAD patients