Correlation between soluble receptor for advanced glycation end products levels and coronary artery disease in postmenopausal nondiabetic women

BACKGROUNDThe established cardiovascular risk factors cannot explain the overall risk of coronary artery disease (CAD), especially in women. Therefore, there is a growing need for the assessment of novel biomarkers to identify women at risk. The receptor for advanced glycation end products (RAGE) and its interaction with the advanced glycation end product (AGE) ligand have been associated with atherogenesis. The soluble fraction of RAGE (sRAGE) antagonizes RAGE signaling and exerts an antiatherogenic effect.AIMThe study aim was to explore the association between plasma levels of sRAGE and CAD in nondiabetic postmenopausal women.METHODSThis case-control study included 110 nondiabetic postmenopausal women who were enrolled in two groups. Group I included 55 angiographically proven CAD subjects with > 50% stenosis in at least one of the major coronary arteries and Group II included 55 healthy control women who did not have CAD or had < 50% stenosis of the coronary arteries. Stenosis was confirmed by invasive angiography. Plasma sRAGE was determined by an enzyme-linked immunosorbent assay.RESULTSWe observed significantly lower plasma sRAGE concentrations in subjects with CAD vs healthy controls (P < 0.05). Univariate and multivariate logistic regression analysis also revealed a significant correlation between plasma sRAGE levels and CAD (P = 0.01). Multivariate odds ratios for CAD revealed that subjects with sRAGE concentrations below 225 pg/mL (lowest quartile) had a 6-fold increase in CAD prevalence independent of other risk factors.CONCLUSIONOur findings indicated that low sRAGE levels were independently associated with CAD in nondiabetic postmenopausal women. Risk assessment of CAD in postmenopausal women can be improved by including sRAGE along with other risk factors.     

Primary congenital anomalies of the coronary arteries: a coronary: arteriographic study

Geographic variations in the incidence of different congenital coronary anomalies are well known, but infrequently studied in the Indian population. Among 4,100 adult patients who underwent diagnostic coronary arteriography, 39 (0.95%) patients (34 males, 5 females) had one or more anomalous coronary arteries. Their mean age was 46.4 +/- 8.2 years (range, 26-68 years). Thirty-five (89.74%) had anomalies of origin and distribution, while the remaining four (10.25%) had coronary artery fistulae. Right coronary artery was the commonest anomalous vessel, involved in 19 (48.74%) patients. It was originating from the left sinus of Valsalva in 15 and from the non-facing aortic sinus in four patients. Anomalous left circumflex artery was the second commonest anomaly, seen in 14 (35.89%) patients. Anomalous left anterior descending artery and anomalous left coronary artery from pulmonary artery were seen in one patient each. Among patients with coronary fistulae, two had fistulae between the left anterior descending artery and the main pulmonary artery, one between the conal artery and the right atrium, while the fourth patient had fistulae from the right coronary as well as from the left anterior descending artery to the left atrium. Atherosclerotic plaques in the anomalous arteries were seen in only 13 (33.33%) patients, much less than the overall incidence of coronary artery disease in patients with congenital coronary anomalies in this series (66.66%). In four (10.25%) patients, only the anomalous vessels were involved in coronary artery disease. Thus, in a small subgroup there does not appear to be an increased risk for development of atherosclerotic coronary artery disease in anomalous coronary arteries. Recognition of coronary anomalies is important in patients undergoing coronary arteriography, coronary interventions and cardiac surgery. Variations in the frequency of primary congenital coronary anomalies may possibly have a genetic background.     

Study of Three Cases of Primary Refractory T Cell ALL

A significant proportion of T cell acute lymphoblastic leukemia (T-ALL) patients do not achieve complete remission after 4 weeks of induction chemotherapy or relapse early. Salvage chemotherapy for such patients usually results in poor outcome which can be up to 20–30% survival with allogeneic BMT. Nelarabine combined with chemotherapy, in COG AALL0434 study, showed 4-year disease-free survival of 54.8% in patients with primary refractory T ALL. An allogeneic BMT in such patients may further improve outcome. In this report, three patients with primary refractory T cell ALL including a case of ETP-ALL and near ETP-ALL were treated with Nelarabine combined with COG based regime and thereafter an allogeneic stem cell transplantation. All three patients achieved a complete remission with negative minimal residual disease status with one course of therapy, received allo SCT (MSD = 2, Haplo = 1) and are surviving in complete remission at 12 months, 14 months and 25 months of follow up. This report highlights that primary refractory T ALL patient can be successfully treated with Nelarabine in combination with chemotherapy and consolidation with allogeneic SCT to provide maximum chances of long-term survival and cure.     

Protease,Growth Factor,and Heparanase-Mediated Syndecan-1 Shedding Leads to Enhanced HSV-1 Egress

Heparan sulfate (HS) and heparan sulfate proteoglycans (HSPGs) are considered important for the entry of many different viruses. Previously, we demonstrated that heparanase (HPSE), the host enzyme responsible for cleaving HS chains, is upregulated by herpes simplex virus-1 (HSV-1) infection. Higher levels of HPSE accelerate HS removal from the cell surface, facilitating viral release from infected cells. Here, we study the effects of overexpressing HPSE on viral entry, cell-to-cell fusion, plaque formation, and viral egress. We provide new information that higher levels of HPSE reduce syncytial plaque formation while promoting egress and extracellular release of the virions. We also found that transiently enhanced expression of HPSE did not affect HSV-1 entry into host cells or HSV-1-induced cell-to-cell fusion, suggesting that HPSE activation is tightly regulated and facilitates extracellular release of the maturing virions. We demonstrate that an HSPG-shedding agonist, PMA; a protease, thrombin; and a growth factor, EGF as well as bacterially produced recombinant heparinases resulted in enhanced HSV-1 release from HeLa and human corneal epithelial (HCE) cells. Our findings here underscore the significance of syndecan-1 functions in the HSV-1 lifecycle, provide evidence that the shedding of syndecan-1 ectodomain is another way HPSE works to facilitate HSV-1 release, and add new evidence on the significance of various HSPG shedding agonists in HSV-1 release from infected cells.     

Successful balloon mitral valvotomy in rheumatic mitral stenosis with Ebstein's anomaly

The association of Ebstein's anomaly of tricuspid valve with rheumatic mitral stenosis is extremely rare. The case is presented of a young female who had been admitted with progressive dyspnea secondary to severe rheumatic mitral stenosis with moderate pulmonary hypertension, along with Ebstein's anomaly of tricuspid valve. The patient underwent successful balloon mitral valvotomy, using the Inoue technique, with a marked improvement in her symptoms.     

Diacylglycerol promotes centrosome polarization in T cells via reciprocal localization of dynein and myosin II

Centrosome reorientation to the immunological synapse maintains the specificity of T-cell effector function by facilitating the directional release of cytokines and cytolytic factors toward the antigen-presenting cell. This polarization response is driven by the localized accumulation of diacylglycerol, which recruits multiple protein kinase (PK)C isozymes to the synaptic membrane. Here, we used T-cell receptor (TCR) photoactivation and imaging methodology to demonstrate that PKCs control centrosome dynamics through the reciprocal localization of two motor complexes, dynein and nonmuscle myosin (NM)II. Dynein accumulated in the region of TCR stimulation, whereas NMII clustered in the back of the cell, behind the polarizing centrosome. PKC activity, which shaped both dynein and NMII accumulation within this framework, controlled NMII localization directly by phosphorylating inhibitory sites within the myosin regulatory light chain, thereby suppressing NMII clustering in the region of TCR stimulation. Concurrently, phosphorylation of distinct sites within myosin regulatory light chain by Rho kinase drove NMII clustering in areas behind the centrosome. These results reveal a role for NMII in T-cell polarity and demonstrate how it is regulated by upstream signals.     

Revealing conformational substates of lipidated N-Ras protein by pressure modulation

Regulation of protein function is often linked to a conformational switch triggered by chemical or physical signals. To evaluate such conformational changes and to elucidate the underlying molecular mechanisms of subsequent protein function, experimental identification of conformational substates and characterization of conformational equilibria are mandatory. We apply pressure modulation in combination with FTIR spectroscopy to reveal equilibria between spectroscopically resolved substates of the lipidated signaling protein N-Ras. Pressure has the advantage that its thermodynamic conjugate is volume, a parameter that is directly related to structure. The conformational dynamics of N-Ras in its different nucleotide binding states in the absence and presence of a model biomembrane was probed by pressure perturbation. We show that not only nucleotide binding but also the presence of the membrane has a drastic effect on the conformational dynamics and selection of conformational substates of the protein, and a new substate appearing upon membrane binding could be uncovered. Population of this new substate is accompanied by structural reorientations of the G domain, as also indicated by complementary ATR-FTIR and IRRAS measurements. These findings thus illustrate that the membrane controls signaling conformations by acting as an effective interaction partner, which has consequences for the G-domain orientation of membrane-associated N-Ras, which in turn is known to be critical for its effector and modulator interactions. Finally, these results provide insights into the influence of pressure on Ras-controlled signaling events in organisms living under extreme environmental conditions as they are encountered in the deep sea where pressures reach the kbar range.     

Acute ST-elevation myocardial infarction 6 years following a sirolimus-eluting stent secondary to complete stent fracture

With increasing coronary interventions, coronary stent fracture following implantation of drug-eluting stents is being commonly recognized. Though isolated strut fractures are often only incidental findings, more severe forms of stent fracture with complete transection have adverse clinical outcomes. Most such cases are reported within several months following the index angioplasty. We report an unusual presentation of late stent fracture following a sirolimus-eluting stent, presenting with acute myocardial infarction 6 years after the initial stent implantation. The various mechanisms underlying fracture of drug-eluting stents are reviewed. Because no known mechanisms were noted in our case, unknown factors may also play a role in the genesis of stent fracture. Clinicians need to be aware that such complications may present rarely, extremely late after the index procedure as an acute myocardial infarction.     

Hospitalized pneumonia

OBJECTIVES: To describe discharge rates, geographic and patient characteristics, treatment patterns, costs, and outcomes of patients hospitalized with community-acquired pneumonia (CAP) in Pennsylvania hospitals and compare these patients from rural and urban counties. DESIGN: A retrospective database study. PATIENTS: Adult patients (age ≥18) with an ICD-9-CM diagnosis of pneumonia discharged from 193 Pennsylvania hospitals (n=36,222) in 1991 from the MediQual Systems Pennsylvania database. MEASUREMENTS: Patient characteristics included a pneumonia-specific severity index, microbiologic etiology, and a number of comorbid conditions. Treatment indicators included the specialty of the admitting physician, length of stay, admittance to an intensive care unit, and mechanical ventilation. Cost indicators included charges and estimated costs. Outcomes measured were inpatient mortality and discharge disposition. Counties in Pennsylvania were classified into seven urban or rural groups, and patients were classified by the county of residence. RESULTS: The discharge rate for CAP was 4.0 per 1,000 and did not vary systematically across urban or rural counties. Most patients were treated in local hospitals. The average distance between residence and hospital was 5.4 miles and varied with urban or rural classification (range 2.5–9.3 miles). Among CAP patients, 37.8% were at low risk of mortality, with no systematic differences across rural or urban patients with respect to pneumonia severity. Rural patients were more likely to be treated by a family physician and somewhat less likely to be admitted to an intensive care unit or to be mechanically ventilated. Costs of treating rural patients were lower. In-hospital mortality rates, with controls for admission severity, were comparable or better for rural patients than for urban patients. CONCLUSIONS: Patients with CAP are treated in hospitals located in counties similar to ones in which they reside. The cost of treatment was lower for rural patients than for urban patients, but outcomes were not different. This work was funded in part by the Agency for Health Care Policy and Research (R01 HSO 6468) as part of the Pneumonia Patient Outcomes Research Team (PORT) Project. Dr. Fine is supported in part as a Robert Wood Johnson Foundation Generalist Faculty Scholar.