Prognostic effect of coronary flow reserve in women versus men with chest pain syndrome and normal dipyridamole stress echocardiography

The aim of this study was to investigate the prognostic effect of coronary flow reserve (CFR) on left anterior descending artery (LAD) in women and men with chest pain of unknown origin and normal stress echocardiogram. The study population consisted of 1,660 patients (906 women, 754 men) with chest pain syndrome, no wall motion abnormality on echocardiogram at rest, and dipyridamole (up to 0.84 mg/kg over 6 minutes) stress echocardiogram negative for wall motion criteria. All had undergone stress echocardiography with combined evaluation of CFR on LAD by Doppler. A CFR value ≤2.0 was considered abnormal. Median duration of follow-up was 19 months (interquartile range 10 to 34). Abnormal CFR was assessed in 171 women (19%) and 147 men (19%, p = 0.80). During follow-up, 80 events (20 deaths, 13 ST-elevation myocardial infarctions, and 47 non-ST-elevation myocardial infarctions) occurred. In addition, 128 patients underwent revascularization and were censored. CFR ≤2.0 on LAD was independently associated with prognosis in women (hazard ratio [HR] 16.48, 95% confidence interval [CI] 7.17 to 37.85, p <0.0001) and in men (HR 6.23, 95% CI 3.42 to 11.33, p <0.0001). Antianginal therapy at time of testing (HR 2.11, 95% CI 1.14 to 3.90, p = 0.02) was also a multivariable prognostic predictor in men. Four-year event rate associated with CFR values ≤2.0 and >2.0 were, respectively, 27% and 2% in women (p <0.0001) and 42% and 8% in men (p <0.0001). In conclusion, decreased CFR on LAD is associated with markedly increased risk in women and men with chest pain syndrome and a normal result of dipyridamole stress echocardiography. Conversely, preserved CFR on LAD predicts excellent survival, particularly in women.     

Altering dietary lysine:arginine ratio has little effect on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults

BackgroundInformation is scarce regarding the effect of dietary protein type, with specific focus on the lysine-to-arginine (Lys:Arg) ratio, on cardiovascular risk factors and vascular reactivity in humans.ObjectiveDetermine the effect of dietary Lys:Arg ratio on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults.DesignRandomized cross-over design of two 35-day diet phases; thirty adults (21 females and 9 males, ≥50 years, LDL cholesterol ≥120 mg/dL). Diets had 20% energy (E) protein, 30% E fat, 50% E carbohydrate and were designed to have low (0.7) or high (1.4) Lys:Arg ratio. Measures included fasting and postprandial lipid, lipoprotein, apolipoprotein concentrations; fasting high sensitivity C-reactive protein (hsCRP), small dense LDL (sdLDL) cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities; cholesterol fractional synthesis rate (FSR); and flow mediated dilation (FMD) and peripheral artery tonometry (PAT).ResultsNo differences were observed in fasting and/or postprandial total, LDL, HDL and sdLDL cholesterol, RemLC, Lp(a) or apo B concentrations, LCAT and CETP activities, FSR, glycated albumin, immunoreactive insulin, FMD or PAT. The low, relative to the high, Lys:Arg ratio diet resulted in lower postprandial VLDL cholesterol (?24%, P = 0.001) and triglycerides (?23%, P = 0.001), and small but significant differences in fasting (?3%, P = 0.003) and postprandial (?3%, P = 0.018) apo AI, and fasting adiponectin concentrations (+7%, P = 0.035). Fasting and postprandial hsCRP concentrations were 23% lower after the low Lys:Arg ratio diet (P = 0.020 for both).ConclusionsDiets differing in Lys:Arg ratios had no or small effects on cardiovascular risk factors and vascular reactivity.     

Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease

Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-β family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox–5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.     

Fitting a xenobiotic receptor into cell homeostasis: how the dioxin receptor interacts with TGFbeta signaling

As our knowledge on the mechanisms that control cell function increases, more complex signaling pathways and quite intricate cross-talks among regulatory proteins are discovered. Establishing accurate interactions between cellular networks is essential for a healthy cell and different alterations in signaling are known to underline human disease. Transforming growth factor beta (TGFbeta) is an extracellular cytokine that regulates such critical cellular responses as proliferation, apoptosis, differentiation, angiogenesis and migration, and it is assumed that the latency-associated protein LTBP-1 plays a relevant role in TGFbeta targeting and activation in the extracellular matrix (ECM). The dioxin receptor (AhR) is a unique intracellular protein long studied because of its critical role in xenobiotic-induced toxicity and carcinogenesis. Yet, a large set of studies performed in cellular systems and in vivo animal models have suggested important xenobiotic-independent functions for AhR in cell proliferation, differentiation and migration and in tissue homeostasis. Remarkably, AhR activity converges with TGFbeta-dependent signaling through LTBP-1 since cells lacking AhR expression have phenotypic alterations that can be explained, at least in part, by the coordinated regulation of both proteins. Here, we will discuss the existence of functional interactions between AhR and TGFbeta signaling. We will focus on regulatory and functional aspects by analyzing how AhR status determines TGFbeta activity and by proposing a mechanism through which LTBP-1, a novel AhR target gene, mediates such effects. We will integrate ECM proteases in the AhR-LTBP-1-TGFbeta axis and suggest a model that could help explain some in vivo phenotypes associated to AhR deficiency.     

Strategies for electrochemical detection in immunochemistry

In this review, the current status of research in electrochemical immunosensors is considered. We primarily focus on label-free and enzyme-labeled immunosensors, and the analytical capabilities of these devices are discussed. Moreover, the use of magnetic beads as new materials for immunosensors coupled with electrochemical sensing is also described, together with the application of new molecules such as aptamers as specific biorecognition elements. Examples of the applicability of these devices in solving various analytical problems in clinical, environmental and food fields are reported. Finally, the prospects for the further development of immunosensor technologies are shown.     

Performance characteristics of the Architect brain natriuretic peptide (BNP) assay: a two site study

INTRODUCTION: Brain natriuretic peptide (BNP) is produced by the ventricles of the heart and is a biomarker for heart failure. Several commercial assays are now available. We evaluated the performance characteristics of the ARCHITECT BNP assay. METHODS: We evaluated the limit of blank, limit of detection, linearity and imprecision. Method comparison studies were performed with 3 other automated BNP assays including the ADVIA Centaur, AxSYM, and UniCel DxI 800 methods. RESULTS: The mean LOB and LOD of the Architect assay were 3.5 and 5.8 ng/L, respectively. Imprecision studies yielded within run CVs of 1.1 to 5.1% and total CVs of 2.3 to 5.3% using human plasma based multi-constituent controls at concentrations of 92, 500, and 3500 ng/L. The maximum deviation from the target recovery for dilution linearity was 9.6%. Concordance with other BNP assays at a 100 ng/l cutoff was 91 to 98% and kappa statistics were 0.78 to 0.96. The mean difference between the Architect and Advia Centaur methods was positive. For the other methods, the mean difference with the Architect was negative. CONCLUSIONS: The Architect BNP assay shows good performance characteristics with total imprecision < or =5.3%. It agrees well with the Advia Centaur, AxSYM, and UniCel DxI BNP assays.     

Reduced allergic lung inflammation in rats following formaldehyde exposure: Long-term effects on multiple effector systems

Clinical and experimental evidences show that formaldehyde (FA) exposure has an irritant effect on the upper airways. As being an indoor and outdoor pollutant, FA is known to be a causal factor of occupational asthma. This study aimed to investigate the repercussion of FA exposure on the course of a lung allergic process triggered by an antigen unrelated to FA. For this purpose, male Wistar rats were subjected to FA inhalation for 3 consecutive days (1%, 90-min daily), subsequently sensitized with ovalbumin (OVA)-alum via the intraperitoneal route, and 2 weeks later challenged with aerosolized OVA. The OVA challenge in rats after FA inhalation (FA/OVA group) evoked a low-intensity lung inflammation as indicated by the reduced enumerated number of inflammatory cells in bronchoalveolar lavage as compared to FA-untreated allergic rats (OVA/OVA group). Treatment with FA also reduced the number of bone marrow cells and blood leukocytes in sensitized animals challenged with OVA, which suggests that the effects of FA had not been only localized to the airways. As indicated by passive cutaneous anaphylactic reaction, FA treatment did not impair the anti-OVA IgE synthesis, but reduced the magnitude of OVA challenge-induced mast cell degranulation. Moreover, FA treatment was associated to a diminished lung expression of PECAM-1 (platelet-endothelial cell adhesion molecule 1) in lung endothelial cells after OVA challenge and an exacerbated release of nitrites by BAL-cultured cells. Keeping in mind that rats subjected solely to either FA or OVA challenge were able to significantly increase the cell influx into lung, our study shows that FA inhalation triggers long-lasting effects that affect multiple mediator systems associated to OVA-induced allergic lung such as the reduction of mast cells activation, PECAM-1 expression and exacerbation of NO generation, thereby contributing to the decrease of cell recruitment after the OVA challenge. In conclusion, repeated expositions to air-borne FA may impair the lung cell recruitment after an allergic stimulus, thereby leading to a non-responsive condition against inflammatory stimuli likely those where mast cells are involved.