Coronary artery disease in congenital single coronary artery in adults:A Dutch case series

AIM:To assess the current diagnostic and therapeutic management and the clinical implications of congenital single coronary artery(SCA) in adults.METHODS:We identified 15 patients with a SCA detected from four Dutch angiography centers in the period between 2010 and 2013.Symptomatic patients who underwent routine diagnostic coronary angiography(CAG) for suspected coronary artery disease and who incidentally were found to have isolated SCA were analyzed.RESULTS:Fifteen(7 females) with a mean age of 58.5 ± 13.78 years(range 43-86) had a SCA.ConventionalCAG demonstrated congenital isolated SCA originating as a single ostium from the right sinus of Valsalva in 6 patients and originating from the left in 9 patients.Minimal to moderate coronary atherosclerotic changes were found in 4,and severe stenotic lesions in another 4 patients.Seven patients were free of coronary atherosclerosis.Runs of non-sustained ventricular tachycardia were documented in 2 patients,one of whom demonstrated transmural ischemic changes on presentation.Myocardial perfusion scintigraphic evidence of transmural myocardial ischemia was found in 1 patient due to kinking and squeezing of the SCA with an interarterial course between the aorta and pulmonary artery.Multi-slice computed tomography(MSCT) was helpful to delineate the course of the anomalous artery relative to the aorta and pulmonary artery.Percutaneous coronary intervention was successfully performed in 3 patients.Eight patients were managed medically.Arterial bypass graft was performed in 4 patients with the squeezed SCA.CONCLUSION:SCA may be associated with transient transmural myocardial ischemia and aborted sudden death in the absence of coronary atherosclerosis.The availability and sophistication of MSCT facilitates the delineation of the course of a SCA.We present a Dutch case series and review of the literature.     

Human umbilical vein endothelial cells display high-affinity c-kit receptors and produce a soluble form of the c-kit receptor

Stem cell factor (SCF) is a hematopoietic growth factor produced by fibroblasts and endothelial cells that stimulates the growth of primitive hematopoietic cells. SCF triggers cell growth by binding to the c-kit receptor. Because endothelial cells can respond to certain hematopoietic growth factors, we tested human umbilical vein endothelial cells for display of the c-kit receptor and examined the effect of SCF on endothelial cell proliferation, adhesion molecule expression, and production of tissue factor. Quantitative binding experiments with 125I-SCF showed both high-affinity (Kd = 42 pmol/L) and low-affinity (Kd = 1.7 nmol/L) c-kit receptors. There were approximately 1,100 high-affinity c-kit receptors, and 5,400 low- affinity c-kit receptors per endothelial cell. Enzyme immunoassays showed that endothelial cells released soluble c-kit receptor and SCF. The transmembrane form of SCF was detected by indirect immunofluorescence analysis using monoclonal or polyclonal anti-SCF receptor antibodies. The addition of SCF (100 ng/mL) did not alter endothelial cell proliferation over a 7-day period. Similarly, there was no change in the release of tissue factor or expression of inducible endothelial adhesion molecules (intercellular adhesion molecule-1, endothelial-leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1) measured by enzyme-linked immunosorbant assay at 4 and 24 hours after SCF addition. The neutralizing anti-c-kit receptor monoclonal antibody SR-1 blocked binding of 125I-SCF to the c- kit receptor by 98% but did not alter endothelial cell proliferation or adhesion-molecule expression. c-kit receptors were also detected on adult endothelial cells lining small blood vessels in normal human lymph nodes. These data indicate that normal human endothelial cells produce SCF and show high-affinity c-kit receptors that have the capacity to dimerize. The lack of response to exogenous SCF may be because of intracellular activation of the c-kit receptor via autocrine production of SCF. Alternatively, SCF and c-kit may play a role other than stimulation of proliferation, adhesion-molecule display, or tissue factor production by endothelial cells. The production of soluble c-kit receptors by normal human endothelial cells may serve to regulate the bioactivity of SCF within the bone marrow microenvironment.     

Recombinant human interleukin-3 and granulocyte-macrophage colony- stimulating factor show common biological effects and binding characteristics on human monocytes

Two human hemopoietic growth factors involved in monocytopoiesis, interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were studied for their ability to stimulate blood monocytes and to bind to the monocyte membrane. Both cytokines maintained monocyte/macrophage numbers during long-term culture and increased cell size as compared with controls. Effects on cell numbers were present at low cytokine concentrations (6 to 20 pmol/L), whereas enhanced 3H-thymidine incorporation was observed only at higher concentrations (greater than or equal to 60 pmol/L). Autoradiographic studies showed only 1% to 3% of stimulated monocytes with nuclear grains. These results suggest that the primary mechanism for IL-3 and GM-CSF-induced maintenance of monocyte/macrophage numbers in humans is through an effect on cell survival. Surface receptors for both IL-3 and GM-CSF were studied by using 125I-labeled recombinant human (rh) cytokines and performing Scatchard analyses. Both cytokines showed curvilinear Scatchard plots, and computer analyses favored a two-site binding model. High-affinity binding data for 125I rhIL-3 (Kd 7.7 to 38.2 pmol/L; receptor number/cell 95 to 580) and for 125I rhGM-CSF (Kd 4.7 to 38.9 pmol/L; receptor number/cell 8 to 67) show similar binding affinities for the two cytokines but a lower receptor number/cell for 125I rhGM-CSF. Low-affinity binding characteristics for 125I rhIL-3 (Kd 513 to 939 pmol/L; receptor number/cell 179 to 5,274) and for 125I rhGM- CSF (Kd 576 to 1,120 pmol/L; receptor number/cell 130 to 657) show a similar pattern for the two cytokines. Specificity of 125I rhIL-3 and 125I rhGM-CSF binding to monocytes was established by the ability of the homologous cytokine to inhibit binding and the inability of a range of other cytokines to compete at 100-fold excess molar concentration. It is important, however, that binding of 125I rhIL-3 was partially inhibited by rhGM-CSF and that rhIL-3 partially inhibited binding of 125I rhGM-CSF to the monocyte membrane under conditions shown to prevent receptor internalization. The degree of inhibition varied between 25% and 80% in different experiments, and quantitative inhibition experiments showed that 1,000-fold excess concentrations of competitor failed to inhibit binding of the heterologous ligand completely. These results demonstrate that human IL-3 and GM-CSF have similar effects on growth and survival of human monocytes in vitro and suggest that these and other common biological effects may be mediated either through a common receptor or through distinct receptors associated on the monocyte membrane.     

The detection of specific antibody formation to recall antigens after human bone marrow transplantation

The results of this study show that donor-derived immunity can be detected and persists in long-term survivors with and without chronic graft-v-host disease (GVHD) after human marrow grafting. Seventy-one marrow recipients (60 long-term and 11 short-term survivors) were studied for the presence of specific serum IgG antibodies to tetanus toxoid (TT), and 46 marrow recipients (35 long-term and 11 short-term) were tested for antibodies to diphtheria toxoid (DT) and measles virus after marrow grafting using an enzyme-linked immunosorbent assay. Of the 60 long-term survivors, 31 were healthy and 29 had chronic GVHD. None of the recipients were immunized to the test antigens postgrafting. Most long-term healthy recipients exhibited antibody titers to the recall test antigens, whereas only a minority of those with chronic GVHD had antibody titers to recall antigens. In healthy long-term recipients (greater than or equal to one year postgrafting) whose donors were immune to the test antigens, 25 of 31 had titers to TT, 11 of 17 had titers to DT, and 12 of 20 had titers to measles. In recipients with C-GVHD, 13 of 29 had titers to TT, six of 15 had titers to DT, and six of 15 had titers to measles virus. Within 100 days postgrafting, 11 of 11 had anti-TT titers, ten of ten had anti-DT titers, and seven of eight had antimeasles virus titers.     

短暂性脑缺血发作病因诊断的评估

短暂性脑缺血发作病因诊断的评估魏岗之缺血性脑血管意外是中国老人致死和致残的主要原因，短暂性脑缺血发作（ＴＩＡ）是脑血管意外的警告信号。其中约有１／３将发展为脑血管意外，一次ＴＩＡ预示有罹患脑血管意外的危险，因而能使医生在发病前进行干预。ＴＩＡ是由于血...     

National Release of the Nursing Home Quality Report Cards: Implications of Statistical Methodology for Risk Adjustment

Objective. To determine how alternative statistical risk-adjustment methods may affect the quality measures (QMs) in nursing home (NH) report cards.
Data Sources/Study Settings. Secondary data from the national Minimum Data Set files of 2004 and 2005 that include 605,433 long-term residents in 9,336 facilities.
Study Design. We estimated risk-adjusted QMs of decline in activities of daily living (ADL) functioning using classical, fixed-effects, and random-effects logistic models. Risk-adjusted QMs were compared with each other, and with the published QM (unadjusted) in identifying high- and low-quality facilities by either the rankings or 95 percent confidence intervals of QMs.
Principal Findings. Risk-adjusted QMs showed better overall agreement (or convergent validity) with each other than did the unadjusted versus each adjusted QM; the disagreement rate between unadjusted and adjusted QM can be as high as 48 percent. The risk-adjusted QM derived from the random-effects shrinkage estimator deviated nonrandomly from other risk-adjusted estimates in identifying the best 10 percent facilities using rankings.
Conclusions. The extensively risk-adjusted QMs of ADL decline, even when estimated by alternative statistical methods, show higher convergent validity and provide more robust NH comparisons than the unadjusted QM. Outcome rankings based on ADL decline tend to show lower convergent validity when estimated by the shrinkage estimator rather than other statistical methods.     

Impact of changing the statistical methodology on hospital and surgeon ranking: the case of the New York State cardiac surgery report card

BACKGROUND: Risk adjustment is central to the generation of health outcome report cards. It is unclear, however, whether risk adjustment should be based on standard logistic regression, fixed-effects or random-effects modeling. OBJECTIVE: The objective of this study was to determine how robust the New York State (NYS) Coronary Artery Bypass Graft (CABG) Surgery Report Card is to changes in the underlying statistical methodology. METHODS: Retrospective cohort study based on data from the NYS Cardiac Surgery Reporting System on all patient undergoing isolated CABG surgery in NYS and who were discharged between 1997 and 1999 (51,750 patients). Using the same risk factors as in the NYS models, fixed-effects and random-effects models were fitted to the NYS data. Quality outliers were identified using 1) the ratio of observed-to-expected mortality rates (O/E ratio) and confidence intervals (CIs) calculated using both parametric (Poisson distribution) and nonparametric (bootstrapping) techniques; and 2) shrinkage estimators. RESULTS: At the surgeon level, the standard logistic regression model, the fixed-effects model, and the fixed-effects component of the random-effects model demonstrated near-perfect agreement on the identity of quality outliers using a quality indicator based on the O/E ratio and the Poisson distribution. Shrinkage estimators identified the fewest outliers, whereas the O/E ratios with bootstrap CI identified the greatest number of outliers. The results were similar for hospitals, except that the fixed-effects model identified more outliers than either the NYS model or the fixed-effects component of the random-effects model. CONCLUSION: Shrinkage estimators based on random-effects models are slightly more conservative in identifying quality outliers compared with the traditional approach based on fixed-effects modeling and standard regression. Explicitly modeling surgeon provider effect (fixed-effects and random-effects models) did not significantly alter the distribution of quality outliers when compared with standard logistic regression (which does not model provider effect). Compared with the standard parametric approach, the use of a bootstrap approach to construct 95% confidence interval around the O/E ratio resulted in more providers being identified as quality outliers.     

BB-10010: an active variant of human macrophage inflammatory protein-1 alpha with improved pharmaceutical properties

The stem cell inhibitor, macrophage inflammatory protein-1 alpha (MIP-1 alpha) or LD78, protects multipotent hematopoietic progenitors in murine models from the cytotoxic effects of chemotherapy. Clinical use of human MIP-1 alpha during chemotherapy could therefore lead to faster hematologic recovery and may allow dose intensification. We have also shown that human MIP-1 alpha causes the rapid mobilization of hematopoietic cells, suggesting an additional clinical use in peripheral blood stem cell transplantation. However, the clinical evaluation of human MIP-1 alpha is complicated by its tendency to associate and form high molecular weight polymers. We have produced a variant of rhMIP-1 alpha, BB-10010, carrying a single amino acid substitution of Asp26 > Ala, with a reduced tendency to form large polymers at physiologic pH and ionic strength. This greatly increases its solubility, facilitating its production and clinical formulation. We confirmed the potency of BB-10010 as a human MIP-1 alpha-like agonist in receptor binding, calcium mobilization, inhibition of colony formation, and thymidine suicide assays. The myeloprotective activity of BB-10010 was shown in a murine model of repeated chemotherapy using hydroxyurea. BB-10010 is therefore an ideal variant with which to evaluate the therapeutic potential of recombinant human MIP-1 alpha.