Predicting blood pressure (BP) response to antihypertensive therapy is challenging. The therapeutic intensity score (TIS) is a summary measure that accounts for the number of medications and the relative doses a patient received, but its relationship to BP change and its utility as a method to project dosing equivalence has not been reported. We conducted a prospective, single center, randomized controlled trial to compare the effects of Joint National Committee (JNC) 7 compliant treatment with more intensive (<120/80 mm Hg) BP goals on left ventricular structure and function in hypertensive patients with echocardiographically determined subclinical heart disease who were treated over a 12-month period. For this preplanned subanalysis, we sought to compare changes in BP over time with changes in TIS. Antihypertensive therapy was open label. TIS and BP were determined at 3-month intervals with titration of medication doses as needed to achieve targeted BP. Mixed linear models defined antihypertensive medication TIS as an independent variable and change in systolic BP as an outcome measure, while controlling for gender, age, baseline BP, and treatment group. A total of 123 patients (mean age 49.4 ± 8.2 years; 66% female; 95.1% African-American) were enrolled and 88 completed the protocol. For each single point increase in total antihypertensive TIS, a 14.5 (95% confidence interval: 11.5, 17.4) mm Hg decrease in systolic BP was noted (15.5 [95% confidence interval: 13.0, 18.0] mm Hg for those who completed the trial). Total TIS is a viable indicator of the anticipated BP-lowering effect associated with antihypertensive therapy.
Protein-disulfide isomerase (PDI), an endoplasmic reticulum (ER)-resident protein, is primarily known as a catalyst of oxidative protein folding but also has a protein unfolding activity. We showed previously that PDI unfolds the cholera toxin A1 (CTA1) polypeptide to facilitate the ER-to-cytosol retrotranslocation of the toxin during intoxication. We now provide insight into the mechanism of this unfoldase activity. PDI includes two redox-active (a and a) and two redox-inactive (b and b) thioredoxin-like domains, a linker (x), and a C-terminal domain (c) arranged as abbxac. Using recombinant PDI fragments, we show that binding of CTA1 by the continuous PDIbbxa fragment is necessary and sufficient to trigger unfolding. The specific linear arrangement of bbxa and the type a domain (a versus a) C-terminal to bbx are additional determinants of activity. These data suggest a general mechanism for the unfoldase activity of PDI: the concurrent and specific binding of bbxa to particular regions along the CTA1 molecule triggers its unfolding. Furthermore, we show the bb domains of PDI are indispensable to the unfolding reaction, whereas the function of its a domain can be substituted partially by the a domain from ERp57 (abbxac) or ERp72 (ca°abbxa), PDI-like proteins that do not unfold CTA1 normally. However, the bb domains of PDI were insufficient to convert full-length ERp57 into an unfoldase because the a domain of ERp57 inhibited toxin binding. Thus, we propose that generating an unfoldase from thioredoxinlike domains requires the bb(x) domains of PDI followed by an a domain but not preceded by an inhibitory a domain. Protein-disulfide isomerase (PDI)2 is a multifunctional protein that resides in the endoplasmic reticulum (ER) lumen of all eukaryotic cells (reviewed in Ref. 1). Mammalian PDI was first identified as a catalyst of oxidative protein folding (2), but it is now also known to mediate viral infection (3, 4), antigen processing (5), collagen assembly (6), and ERassociated degradation (7-9). To participate in this variety of cellular processes, PDI performs multiple activities. For example, during oxidative protein folding, PDI catalyzes the oxidation and isomerization of disulfide bonds and induces conformational changes in non-native polypeptides (10). Independently of redox chemistry, PDI is a molecular chaperone, binding polypeptides to prevent their aggregation (11-13). PDI also acts as a structural subunit of the prolyl 4-hydroxylase (P4H) and microsomal triglyceride transfer protein complexes; however, this function is similar to its chaperone activity (14 -19). In contrast to its protein folding activities, PDI unfolds the catalytic A1 polypeptide of cholera toxin (CTA1) in preparation for the retrotranslocation of the toxin from the ER lumen into the cytosol (8,20).Cholera toxin (CT) is a pathogenic factor that causes secretory diarrhea in animals (reviewed in Ref. 21). The holotoxin includes a single catalytic A subunit (CTA) and a homopentameric B subunit (CTB) joined noncovalently (22). Upon secr...
Objectives: The objective was to evaluate the diagnostic test characteristics of three validated electrocardiographic (ECG) criteria for the diagnosis of left ventricular hypertrophy (LVH) in undifferentiated, asymptomatic emergency department (ED) patients with hypertension (HTN).Methods: This was a prospective cohort study of ED patients with asymptomatic HTN at a single tertiary care facility. Patients 35 years of age or older with systolic blood pressure (sBP) ≥ 140 mm Hg or diastolic blood pressure (dBP) ≥ 90 mm Hg on two separate readings (at least 1 hour apart) were eligible for inclusion. At enrollment, ECGs were obtained for all patients. Presence of LVH on ECG was defined using Cornell voltage, Cornell product, and Minnesota Code 3.1/3.2 criteria. Echocardiography was then performed, with LVH defined by the presence of one or more of the following validated criteria: interventricular septal or posterior wall thickness ≥ 1.3 cm, LV mass ≥ 225 g (male) or ≥ 163 g (female), or LV mass indexed to height raised to the power of 2.7 ≥ 48 g/m 2.7 (male) or ≥ 45 g/m 2.7 (female). Descriptive statistics and diagnostic characteristics (i.e., sensitivity and specificity) with corresponding 95% confidence intervals (CIs) for each of the three ECG criteria were derived for both the composite and the individual echocardiographic determinants of LVH. Logistic regression was also used to model LVH before and after subsequent inclusion of clinically relevant variables.Results: A total of 161 patients (93.8% African American; mean [AESD] age = 49.8 [AE8.3] years) were enrolled, and LVH was present in 89 patients (55.2%, 95% CI = 47.6% to 62.8%). On ECG analysis, mean Cornell voltage (21.5 mV vs. 28.7 mV; difference = -7.2 mV, 95% CI = -3.8 to -10.7 mV) and Cornell product (1868.4 msec 9 mV vs. 2616.4 msec 9 mV; difference = -748.0 msec 9 mV, 95% CI = -401.2 to -1094.8 msec 9 mV) were significantly lower among those without LVH on echocardiography. Subjects without LVH on echocardiography were less likely to meet Cornell voltage (30.5% vs. 48.3%; difference = -17.8%, 95% CI = -2.5% to -31.7%) or Cornell product (26.4% vs. 49.4%; difference = -23.0%, 95% CI = -8.0% to -36.5%) criteria for LVH. The diagnosis of LVH by Minnesota Code was less common (18.1% vs. 25.8%; difference = -7.7%, 95% CI = -20.1% to 5.3%) with no difference by group. Sensitivity and specificity were as follows: for the Cornell voltage, sensitivity 25.4% (95% CI = 15.3% to 37.9%), specificity 50.0% (95% CI = 67.6% to 93.2%); for the Cornell product, sensitivity 25.4% (95% CI = 15.3% to 37.9%), specificity 75.0% (95% CI = 19.4% to 99.4%); and for the Minnesota code, sensitivity 26.9% (95% CI = 16.6% to
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