Step‐by‐step StentBoost‐guided small vessel stenting using the self‐expandable sparrow stent‐in‐wire

A 56 year‐old woman underwent percutaneous coronary intervention for a lesion in a small mid‐left anterior descending coronary artery (reference vessel diameter by quantitative coronary angiography: 2.11 mm) with a novel drug‐eluting stent specifically designed for small vessels, the CardioMind Sparrow stent delivery system. This is a self‐expandable sirolimus‐eluting nitinol stent directly mounted into a 0.014‐inch coronary guidewire. The stent has a very thin strut thickness (67 micron), limiting its radiopacity. A specific X‐ray stent‐enhancing visualization technique, “StentBoost”, allowed clear visualization and understanding of the steps needed for an appropriate release and deployment of the aforementioned stent. © 2008 Wiley‐Liss, Inc.     

Cut‐off value of red‐blood‐cell‐bound IgG for the diagnosis of Coombs‐negative autoimmune hemolytic anemia

Direct antiglobulin test (DAT)‐negative autoimmune hemolytic anemia (Coombs‐negative AIHA) is characterized by laboratory evidence of in vivo hemolysis, together with a negative DAT performed by conventional tube technique (CTT) in clinically suspected AIHA patients. The immunoradiometric assay (IRMA) for red‐blood‐cell‐bound immunoglobulin G (RBC‐IgG) can be used to diagnose patients in whom CTT does not detect low levels of red cell autoantibodies. We investigated the diagnostic cutoff value of the IRMA for RBC‐IgG in Coombs‐negative AIHA and calculated its sensitivity and specificity. Of the 140 patients with negative DAT by CTT referred to our laboratory with undiagnosed hemolytic anemia, AIHA was clinically diagnosed in 64 patients (Coombs‐negative AIHA). The numbers of Coombs‐negative AIHA and non‐AIHA patients changed with age and gender. The cutoff values were determined from receiver operating characteristic (ROC) curve according to age and gender. The IRMA for RBC‐IgG proved to be sensitive (71.4%) and specific (87.8%) when using these cutoffs. Using these cutoffs for 41 patients with negative DAT referred to our laboratory in 2006, all the pseudonegative cases were treated with steroids before the test. The 31 untreated cases could be grouped using one cutoff value of 78.5 and showed 100% sensitivity and 94% specificity, independent of gender and age. Results indicate that RBC‐IgG could become a standard approach for the diagnosis of Coombs‐negative AIHA, when measured before treatment. Am. J. Hematol., 2009. © 2008 Wiley‐Liss, Inc.     

Preclinical anti‐myeloma activity of the novel HDAC‐inhibitor JNJ‐26481585

Pharmacological inhibitors of histone deacetylases (HDACs) are currently being developed and tested as anti‐cancer agents and may be useful to enhance the therapeutic efficiency of established anti‐myeloma treatments. This study preclinically evaluated the effects of the ‘second generation’ pan‐HDAC inhibitor JNJ‐26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n = 42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2‐family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl‐1 depletion and Hsp72 induction were the most reliable features observed in JNJ‐26481585‐treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ‐26481585 with anti‐myeloma therapeutic agents generally resulted In effects close to additivity. In view of the favourable activity of this novel HDAC‐inhibitor towards primary myeloma cells further evaluation in a clinical setting is warranted.     

Another tool for the fork‐in‐the‐road toolbox

• A provisional stent strategy for bifurcation disease is a good rule of thumb.
• The Tryton bifurcation stent is an additional potential useful tool for use in complex coronary disease.
• If and when this device has a drug‐eluting side branch, its true role may be clearer.

     

B‐type natriuretic peptide and C‐terminal‐pro‐endothelin‐1 for the prediction of severely impaired peak oxygen consumption

Objective. To assess the utility of B‐type natriuretic peptide (BNP) and C‐terminal‐pro‐endothelin‐1 (CT‐proET‐1) to predict a severely impaired peak oxygen consumption (peak VO₂, < 14 mL kg^?1 min^?1) in patients referred for cardiopulmonary exercise testing. Design. Cross‐sectional study. Setting. Tertiary care center. Methods. Peak VO₂, BNP and CT‐proET‐1 were assessed in 141 consecutive patients referred for cardiopulmonary exercise testing. Results. B‐type natriuretic peptide [median (interquartile range) 48 (38–319) vs. 33 (15–86) pg mL^?1; P = 0.002] and CT‐proET‐1 [87 (76–95) vs. 60 (52–74) pmol L^?1; P < 0.001] were higher in patients with a peak VO₂ < 14 mL kg^?1 min^?1 (n = 30) than in those with a peak VO₂ ≥ 14 mL kg^?1 min^?1 (n = 111). CT‐pro‐ET‐1 had a higher area under the receiver‐operator‐characteristics curve (AUC) to predict a peak VO₂ < 14 mL kg^?1 min^?1 than BNP (0.79 vs. 0.68; P = 0.04). The optimal BNP cut‐off of 37.2 pg mL^?1 had a sensitivity of 80% and a specificity of 56%. The optimal CT‐proET‐1 cut‐off of 74.4 pmol L^?1 had a sensitivity of 80% and specificity of 76%. A five‐item score composed of body mass index, diabetes, forced expiratory volume within the first second, alveolo–arterial oxygen pressure difference, and BNP had an AUC of 0.88 to predict a peak VO₂ < 14 mL kg^?1 min^?1. Adding CT‐proET‐1 to the score resulted in an AUC of 0.92. Conclusions. C‐terminal‐pro‐endothelin‐1 is superior to BNP for the prediction of a peak VO₂ < 14 mL kg^?1 min^?1 in patients referred for CPET. A score incorporating body mass index, diabetes status, spirometry, blood gases, BNP and CT‐proET‐1 improves the prediction of a peak VO₂ < 14 mL kg^?1 min^?1 based on single biomarkers.     

Glycosylphosphatidylinositol‐anchored high‐density lipoprotein‐binding protein 1 and the intravascular processing of triglyceride‐rich lipoproteins

Lipoprotein lipase (LPL) is produced by parenchymal cells, mainly adipocytes and myocytes, but is involved in hydrolysing triglycerides in plasma lipoproteins at the capillary lumen. For decades, the mechanism by which LPL reaches its site of action in capillaries was unclear, but this mystery was recently solved. Glycosylphosphatidylinositol‐anchored high‐density lipoprotein‐binding protein 1 (GPIHBP1), a glycosylphosphatidylinositol‐anchored protein of capillary endothelial cells, ‘picks up’ LPL from the interstitial spaces and shuttles it across endothelial cells to the capillary lumen. When GPIHBP1 is absent, LPL is mislocalized to the interstitial spaces, leading to severe hypertriglyceridaemia. Some cases of hypertriglyceridaemia in humans are caused by GPIHBP1 mutations that interfere with the ability of GPIHBP1 to bind to LPL, and some are caused by LPL mutations that impair the ability of LPL to bind to GPIHBP1. Here, we review recent progress in understanding the role of GPIHBP1 in health and disease and discuss some of the remaining unresolved issues regarding the processing of triglyceride‐rich lipoproteins.     

Involvement of glucagon‐like peptide‐1 in the glucose‐lowering effect of metformin

Metformin is an oral antihyperglycaemic drug used in the first‐line treatment of type 2 diabetes. Metformin's classic and most well‐known blood glucose‐lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose‐lowering gut incretin hormone glucagon‐like peptide‐1 (GLP‐1), which may contribute to metformin's glucose‐lowering effect in patients with type 2 diabetes. The mechanisms behind metformin‐induced increments in GLP‐1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP‐1 secretion directly and/or indirectly and that metformin prolongs the half‐life of GLP‐1. Also, it has been suggested that metformin may potentiate the glucose‐lowering effects of GLP‐1 by increasing target tissue sensitivity to GLP‐1. The present article critically reviews the possible mechanisms by which metformin may affect GLP‐1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose‐lowering actions of metformin.     

Patient‐reported health‐related quality of life from the phase III TOURMALINE‐MM1 study of ixazomib‐lenalidomide‐dexamethasone versus placebo‐lenalidomide‐dexamethasone in relapsed/refractory multiple myeloma

TOURMALINE‐MM1 is a phase III, randomized, double‐blind, placebo‐controlled study of ixazomib plus lenalidomide and dexamethasone (IRd) versus placebo‐Rd in patients with relapsed/refractory multiple myeloma following 1–3 prior lines of therapy. The study met its primary endpoint, demonstrating significantly longer progression‐free survival (PFS) in the IRd arm versus placebo‐Rd arm (median 20.6 vs 14.7 months, hazard ratio 0.74, P = .01), with limited additional toxicity. Patient‐reported health‐related quality of life (HRQoL) was a secondary endpoint of TOURMALINE‐MM1. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core‐30 (QLQ‐C30) and Multiple Myeloma Module 20 (QLQ‐MY20) were completed at screening, the start of cycles 1 and 2, every other cycle, the end of treatment, and every 4 weeks until progression. Over median follow‐up of 23.3 and 22.9 months in the IRd and placebo‐Rd arms, mean QLQ‐C30 global health status (GHS)/QoL scores were maintained from baseline over the course of treatment in both groups, with no statistically significant differences between groups. EORTC QLQ‐C30 function domain scores were also generally maintained from baseline; similarly, physical, emotional, and social function domains were maintained with IRd versus placebo‐Rd, with slightly higher mean change from baseline scores at earlier time points with IRd. Findings from this double‐blind study demonstrate that addition of ixazomib to Rd significantly improved efficacy while HRQoL was maintained, reflecting the limited additional toxicity seen with IRd versus placebo‐Rd, and support the feasibility of long‐term IRd administration.     

Inhibition of adjuvant‐induced arthritis by DNA vaccination with the 70‐kd or the 90‐kd human heat‐shock protein: Immune cross‐regulation with the 60‐kd heat‐shock protein

Objective

Adjuvant arthritis can be induced in Lewis rats by immunization with Mycobacterium tuberculosis (Mt). The mycobacterial 65‐kd heat‐shock protein (Hsp65) is targeted by arthritogenic T cells. However, Hsp65 and the mycobacterial 71‐kd heat‐shock protein are also recognized by T cells that can down‐regulate adjuvant‐induced arthritis (AIA). We have recently demonstrated that vaccination with human Hsp60 DNA inhibits AIA. The present study was undertaken to analyze the role of the T cell responses to self HSP molecules other than Hsp60 in the control of AIA.

Methods

Lewis rats were immunized with DNA vaccines coding for human Hsp70 or Hsp90 (Hsp70 plasmid [pHsp70] or pHsp90), and AIA was induced. The T cell response to Mt, Hsp60, Hsp70, and Hsp90 (proliferation and cytokine release) was studied, and the T cell response to Hsp60 was mapped with overlapping peptides.

Results

The Hsp70 or Hsp90 DNA vaccines shifted the arthritogenic T cell response from a Th1 to a Th2/3 phenotype and inhibited AIA. We detected immune crosstalk between Hsp70/90 and Hsp60: both the Hsp70 and Hsp90 DNA vaccines induced Hsp60‐specific T cell responses. Similarly, DNA vaccination with Hsp60 induced Hsp70‐specific T cell immunity. Epitope mapping studies revealed that Hsp60‐specific T cells induced by pHsp70 vaccination reacted with known regulatory Hsp60 epitopes.

Conclusion

T cell immunity to Hsp70 and to Hsp90, like Hsp60‐specific immunity, can modulate the arthritogenic response in AIA. In addition, our results suggest that the regulatory mechanisms induced by Hsp60, Hsp70, and Hsp90 are reinforced by an immune network that connects their reactivities.

     

Extended follow‐up safety and effectiveness of the Endeavor zotarolimus‐eluting stent in real‐world clinical practice: Two‐year follow‐up from the E‐Five Registry

Objectives: To present data from the cohort of patients in the all‐comers Endeavor zotarolimus‐eluting stent (ZES) registry (E‐Five) who underwent 2‐year follow‐up. Background: The Endeavor ZES has been shown to be safe and efficacious for treatment of single, de novo lesions in patients with stable coronary artery disease. E‐Five evaluated the ZES in over 8,000 real‐world patients, at 188 sites followed to 1 year. A subset of sites continued follow‐up through 2 years to evaluate late‐term safety and effectiveness of the ZES in this population with diverse clinical and lesion characteristics. Methods: E‐Five, a prospective, multicenter, nonrandomized global registry, collected 2‐year outcomes for 2,116 patients from 26 centers. Sites were selected for participation based on patient accrual rates and the ability to continue follow‐up activities for an additional year. Complete data was available for 2,054 patients. To observe whether or not a sustained benefit was achieved, data for all patients from the selected sites were included in the analysis. Results: The outcomes in the 2‐year cohort tracked with the results of randomized controlled trials using the Endeavor ZES. One year results were MACE 7.5%, TLR 4.5%, and ARC definite/probable stent thrombosis 0.6%. Outcomes at 2 years for MACE, TLR, and ARC definite/probable stent thrombosis were 8.5, 5.1, and 0.7%, respectively. Conclusions: Long‐term efficacy and safety outcomes were maintained between 1 and 2 years for the 2‐year patient cohort, with only a small number of additional MACE, TLR, and very late stent thrombosis events. © 2010 Wiley‐Liss, Inc.