Marinobufagenin,an endogenous ligand of alpha-1 sodium pump,is a marker of congestive heart failure severity

BACKGROUND : A reduced cardiac output in chronic heart failure (CHF) evokes renal NaCl and water retention, and, therefore, activates mechanisms promoting natriuresis. Atrial natriuretic peptide (ANP) is one such factor. We hypothesized that another NaCl sensitive endogenous natriuretic factor, i.e., marinobufagenin (MBG), a specific ligand of the alpha-1 subunit of Na/K ATPase (the main kidney isoform) and also a vasoconstrictor and cardiotonic substance, would be elevated in CHF patients in a graded manner with the severity of CHF. METHODS AND RESULTS : We measured the plasma levels of MBG, alpha-hANP, ouabain-like compound (OLC) and left ventricular (LV) volumes and ejection fraction in 23 consecutive hypertensive male patients with CHF. Plasma MBG levels exhibited progressive increases (0.59 +/- 0.15, 1.08 +/- 0.20, 1.35 +/- 0.17 and 1.88 +/- 0.05 nmol/l NYHA 1-4, respectively) and paralleled the changes of alpha-hANP. Conversely, plasma OLC did not exhibit such increases. Plasma MBG correlated with alpha-hANP (r = 0.82; P < 0.0001). Both MBG and alpha-hANP correlated with LV systolic (r = 0.55 and r = 0.47; P < 0.01) diameter and inversely with ejection fraction (r = -0.73 and r = -0.60; P < 0.01). OLC did not exhibit correlations with alpha-hANP or LV volumes, but positively correlated with systolic brachial blood pressure and with pulse pressure. CONCLUSIONS : In CHF, MBG exhibits progressive increases similar to ANP, varies with CHF severity and correlates with LV systolic function. We hypothesize, that, in CHF, the concurrent production of these two natriuretic hormones, a vasorelaxant, ANP, and a vasoconstrictor, MBG, potentiate each other's natriuretic effects, but may offset their vasoactive actions.     

Clinical characteristics and long-term outcome in patients with heart failure complicating acute myocardial infarction

INTRODUCTION AND OBJECTIVES: To evaluate the clinical characteristics and prognosis of heart failure (HF) development in patients hospitalized for acute myocardial infarction (AMI). PATIENTS AND METHOD: Between May 1990 and March 2000, 836 consecutive patients were admitted with a diagnosis of AMI within 24 h of symptom onset. HF was defined as the presence of rales and a third heart sound with gallop, and evidence of pulmonary congestion on chest x-ray. It was diagnosed in 263 subjects (31.5%). RESULTS: The mean age of patients with HF (group 1) was 63.4 (11.4) years compared with 59.9 (11.6) years in those without HF (group 2) (P<.01). There were differences between groups 1 and 2 in history of diabetes (36% vs 20%; P<.001) or previous HF (9.2% vs 1.1%; P<.001). The reperfusion strategy used in patients with Q-wave infarction, with or without HF, was primary angioplasty in 15% and 14%, respectively (P=.81), and thrombolytic agents in 28% and 37%, respectively (P=.013). Patients with HF were more likely to develop recurrent angina (26.8% vs 19.6%; P=.02), pericarditis (17.5% vs 6.3%; P<.001), and atrial fibrillation (12.3% vs 5.1%; P<.01). In-hospital mortality in groups 1 and 2 was 15.6% and 2.3% (P<.001), respectively, and 10-year survival was 10% and 30%, respectively (P<.001). The variables associated with mortality were: age (HR=1.022; P<.001), hyperglycemia (HR=1.748 per 1.0-g/L increase; P<.001), leukocytosis (HR=1.035 per 1000-cell/.L increase; P<.001), and HF (HR=1.308; P=.028). CONCLUSIONS: AMI is still frequently complicated by HF, which increases short- and long-term morbidity and mortality. Heart failure, age, hyperglycemia, and leukocytosis at admission were independent predictors of mortality during follow-up.     

Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase

OBJECTIVE: To map the antibody response to human citrullinated alpha-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross-reactivity with bacterial enolase. METHODS: Serum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with citrullinated alpha-enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross-reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross-reactivity with bacterial enolase was investigated by immunoblotting. RESULTS: An immunodominant peptide, citrullinated alpha-enolase peptide 1, was identified. Antibodies to this epitope were observed in 37-62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine-containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated alpha-enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2=0.803, P<0.0001). Affinity-purified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis enolase. CONCLUSION: We have identified an immunodominant epitope in citrullinated alpha-enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross-reactivity with bacterial enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.     

A 2-year pilot trial of continuous subcutaneous insulin infusion versus intensive insulin therapy in patients with newly diagnosed type 1 diabetes (IMDIAB 8)

In a pilot study, the metabolic effects of continuous subcutaneous insulin infusion (CSII) versus intensive subcutaneous insulin therapy (ISIT) started at diagnosis in patients with Type 1 diabetes and continued for a 2-year period were evaluated and compared. Twenty-three patients (between 12 and 35 years old, mean +/- SD 18.4 +/- 9 years) were randomized into two treatment groups (CSII vs. ISIT), and both received supplemental nicotinamide (NA), 25 mg/kg of body weight. CSII was started immediately after admission to the hospital. Parameters of metabolic control [insulin dose, hemoglobin A1c (HbA1c), and C-peptide] were evaluated for a 2-year follow-up period. Data are presented for a total of 19 patients who remained in the study for its duration. Two years after diagnosis, mean +/- SD HbA1c was 6.3 +/- 0.5% and 6.2 +/- 0.3% for the CSII and ISIT groups, respectively (p=not significant). Compared with baseline values, an increase of baseline C-peptide of 38% for the CSII group and 27% for the ISIT group was observed; however, the difference between the groups was not significant. The insulin requirement for the entire duration of the study, but not at entry and 3 months, was significantly higher in CSII compared with ISIT patients (0.62 +/- 0.4 IU/kg/day vs. 0.3 +/- 0.4 IU/kg/day, respectively; p<0.01). After trial completion patients on CSII continued with this mode of therapy. Implementation of CSII as well as ISIT at diagnosis of Type 1 diabetes and continuation for 2 years thereafter achieved similar and optimal metabolic control, but more insulin was required with the CSII group. Both types of intensive insulin therapy combined with NA are able to preserve C-peptide secretion or even increase baseline levels for up to 2 years after diagnosis.     

Energetics and Mechanism of Conformational Transitions of Protein‐Like NIPAM‐Sodium Styrene Sulfonate Copolymers in Aqueous Solutions

Protein‐like and random NIPAM‐sodium styrene sulfonate copolymers of similar composition have been prepared by radical polymerization in water at temperatures above and below the LCST of PNIPAM, respectively. Thermal transitions of the copolymers in aqueous solutions have been studied by means of dynamic light scattering, viscometry, and high‐sensitivity differential scanning calorimetry. The phase separation or cooperative conformational transitions without phase separation were observed for the random or the protein‐like copolymers, respectively. Transition temperature, enthalpy, and heat capacity increment of the protein‐like copolymer differed insignificantly from those of the random copolymer of similar composition. The transition heat capacity increments of the protein‐like copolymers revealed that only 10–20% of their NIPAM links participate in the formation of a dense water‐free globule core. The coil–globule transitions of the protein‐like copolymers were described by the thermodynamic three‐state model according to the scheme “random coil?condensed coil?globule”, which is known to simulate the folding mechanism of globular proteins.

     

Predictive ability of the EVARUCI scale and COMHON index for pressure injury risk in critically ill patients: A diagnostic accuracy study

Background

Hospital-acquired pressure injuries are a costly and largely preventable complication occurring in a variety of acute care settings. Patients admitted to the intensive care unit are at greater risk of developing pressure injuries.

Detection of Enzyme Activity and Inhibition during Studies in Solution, <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> with CatalyCEST MRI

Purpose

The detection of enzyme activities and evaluation of enzyme inhibitors have been challenging with magnetic resonance imaging (MRI). To address this need, we have developed a diamagnetic, nonmetallic contrast agent and a protocol known as catalyCEST MRI that uses chemical exchange saturation transfer (CEST) to detect enzyme activity as well as enzyme inhibition.

Procedures

We synthesized a diamagnetic MRI contrast agent that has enzyme responsive and enzyme unresponsive CEST signals. We tested the ability of this agent to detect the activity of kallikrein 6 (KLK6) in biochemical solutions, in vitro and in vivo, with and without a KLK6 inhibitor.

Results

The agent detected KLK6 activity in solution and also detected KLK6 inhibition by antithrombin III. KLK6 activity was detected during in vitro studies with HCT116 colon cancer cells, relative to the detection of almost no activity in a KLK6-knockdown HCT116 cell line and HCT116 cells treated with antithrombin III inhibitor. Finally, strong enzyme activity was detected within an in vivo HCT116 tumor model, while lower enzyme activity was detected in a KLK6 knockdown tumor model and in the HCT116 tumor model treated with antithrombin III inhibitor. In all cases, comparisons of the enzyme responsive and enzyme unresponsive CEST signals were critical for the detection of enzyme activity.

Conclusions

This study has established that catalyCEST MRI with an exogenous diaCEST agent can evaluate enzyme activity and inhibition in solution, in vitro and in vivo.

     

What Factors Are Associated With the Recovery of Autonomy After a Hip Fracture? A Prospective,Multicentric Cohort Study

Objective

To identify the factors associated with recovering autonomy in activities of daily living (ADL) in patients who have had a hip fracture.