New Algorithm for the Prediction of Cardiovascular Risk in Symptomatic Adults with Stable Chest Pain.

PURPOSE OF REVIEW: To review the landmark studies in predicting obstructive coronary artery disease (CAD) in symptomatic patients with stable chest pain and identify better prediction tools and propose a simplified algorithm to guide the health care providers in identifying low risk patients to defer further testing. RECENT FINDINGS: There are a few risk prediction models described for stable chest pain patients including Diamond-Forrester (DF), Duke Clinical Score (DCS), CAD Consortium Basic, Clinical, and Extended models. The CAD Consortium models demonstrated that DF and DCS models overestimate the probability of CAD. All CAD Consortium models performed well in the contemporary population. PROMISE trial secondary data results showed that a clinical tool using readily available ten very low-risk pre-test variables could discriminate low-risk patients to defer further testing safely. In the contemporary population, CAD Consortium Basic or Clinical model could be used with more confidence. Our proposed simple algorithm would guide the physicians in selecting low risk patients who can be managed conservatively with deferred testing strategy. Future research is needed to validate our proposed algorithm to identify the low-risk patients with stable chest pain for whom further testing may not be warranted.

Surface topography of polylactic acid nanofibrous mats: influence on blood compatibility.

Fabricating nanofibrous scaffolds with robust blood compatibility remains an unmet challenge for cardiovascular applications since anti-thrombogenic surface coatings did not withstand physiological shear force. Hence, the present study envisages the influence of smooth and porous topographies of poly(lactic acid) (PLA) nanofibers on hemocompatibility as it could offer time-independent blood compatibility. Further, recent studies have evolved to integrate various contrasting agents for augmenting the prognostic properties of tissue engineered scaffolds; an attempt was also made to synthesize Curcumin-superparamagnetic iron oxide nanoparticle complex (Cur-SPION) as a contrasting agent and impregnated into PLA nanofibers for evaluating the blood compatibility. Herein, electrospun nanofibers of PLA with different topographies (smooth and porous) were fabricated and characterized for surface morphology, zeta potential, fluorescence, and crystallinity. The scaffolds with smooth, porous and rough surface topographies were thoroughly investigated for its hemocompatibility by evaluating hemolysis percentage, platelet adhesion, in vitro kinetic clotting time, serum protein adsorption, plasma recalcification time (PRT), capture and release of erythrocytes. Although the nanofibers of all three groups showed acceptable hemolytic percentage (HP < 5%), the adhered RBCs on Cur-SPION based fibers undergo morphological transformation from biconcave discocytes to echinocytes with cube-like protrusions. On the contrary, no morphological changes were observed in RBCs cultured on smooth and porous nanofibers. Porous fibers exhibited excellent anti-thrombogenic property and adhered lesser platelets and maintained the discoidal morphology of native platelets. Cur-SPION integrated PLA nanofibers showed inactivated platelets with anti-thrombogenic activity compared to smooth nanofibers. In conclusion, PLA nanofibers porous topography did not affect the RBC membrane integrity and maintained discoidal morphology of platelets with superior anti-thrombogenic activity. However, smooth and Cur-SPION integrated PLA nanofibers were found to activate the platelets and deform the RBC membrane integrity, respectively. Hence, the nanofibers with porous structures provide an ideal topography for time-independent hemocompatibility.

Recurrent spontaneous coronary artery dissection: First case report in men with three episodes of spontaneous coronary dissection in separate vascular territories.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. In the literature, more than 1,200 cases of SCAD have been reported, with a low rate of recurrent spontaneous coronary artery dissection (r-SCAD) described in only 63 cases. Among these patients with r-SCAD, just three cases had three separate episodes of dissection and all were in women. We report the first case of r-SCAD in men, with three episodes of dissection in different coronary arteries and review the published literature on predisposing factors for r-SCAD and its management.

Discovery of 2-(1H-indol-5-ylamino)-6-(2,4-difluorophenylsulfonyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (7ao) as a potent selective inhibitor of Polo like kinase 2 (PLK2).

Several families of protein kinases have been shown to play a critical role in the regulation of cell cycle progression, particularly progression through mitosis. These kinase families include the Aurora kinases, the Mps1 gene product and the Polo Like family of protein kinases (PLKs). The PLK family consists of five members and of these, the role of PLK1 in human cancer is well documented. PLK2 (SNK), which is highly homologous to PLK1, has been shown to play a critical role in centriole duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. As a part of our research program, we have developed a library of novel ATP mimetic chemotypes that are cytotoxic against a panel of cancer cell lines. We show that one of these chemotypes, the 6-arylsulfonyl pyridopyrimidinones, induces apoptosis of human tumor cell lines in nanomolar concentrations. The most potent of these compounds, 7ao, was found to be a highly specific inhibitor of PLK2 when profiled against a panel of 288 wild type, 55 mutant and 12 lipid kinases. Here, we describe the synthesis, structure activity relationship, in vitro kinase specificity and biological activity of the lead compound, 7ao.

Hydrothiolation of benzyl mercaptan to arylacetylene: application to the synthesis of (E) and (Z)-isomers of ON 01910·Na (Rigosertib®), a phase III clinical stage anti-cancer agent.

A stereoselective and efficient method for free radical addition of benzyl thiol to aryl acetylene in the presence of Et3B-hexane has been developed for the synthesis of (Z) and (E)-styryl benzyl sulfides where base catalyzed hydrothiolations have failed. The scope of this reaction was successfully extended for the synthesis of (E)-ON 01910·Na, a phase III clinical stage anti-cancer agent and its inactive geometrical isomer (Z)-ON 01910·Na. It is interesting to note that all the E-isomers synthesized have shown better cytotoxicity profile on cancer cells compared to the Z-isomers.

Lipoid proteinosis of Urbach and Weithe: case report and a brief review of the literature.

Lipoid proteinosis is a rare disorder involving multiple organ systems. The ocular manifestations are usually trivial, but greatly aid in the diagnosis. We describe a patient who presented to us with typical moniliform blepharosis. A brief description of relevance to the ophthalmologist and review of the literature follows.

Antibody expression kinetics in glycoengineered Pichia pastoris.

Growth of the antibody market has fueled the development of alternative expression systems such as glycoengineered yeast. Although intact antibody expression levels in excess of 1 g L(-1) have been demonstrated in glycoengineered yeast, this is still significantly below the titers reported for antibody fragments in fungal expression systems. This study presents a simplified approach to estimate antibody secretion kinetics and oxygen uptake rate requirements as a function of growth-rate controlled by a limiting methanol feed rate in glycoengineered Pichia pastoris. The yield of biomass from methanol and the specific oxygen requirements predicted in this study compare well with values reported in the literature for wild-type P. pastoris, indicating the intrinsic nature of these yields independent of glycoengineering or the heterologous protein expressed. Specific productivity was found to be a non-linear function of specific growth rate. Based on comparison with relationships between specific growth rate and specific productivity reported in the literature this correlation seems empirical in nature and cannot be established a priori. These correlations were then used in a simple mass balance based model to predict the cultivation performance of carbon limited cultivations under oxygen transfer limited conditions to indicate the usefulness of this approach to predict large scale performance and aid in process development.

Microbial keratitis after LASIK.

PURPOSE: To report cases of microbial keratitis after LASIK from a tropical climatic zone. METHODS: This retrospective case series included 17 eyes of 15 patients managed at our center from January 1999 to December 2007. All patients had a detailed clinical evaluation followed by corneal scrapings. The material obtained on scraping was subjected to detailed microbiology evaluation. Initial medical treatment was based on microbiology results and included irrigation of the interface with appropriate antimicrobial solutions. The flap was amputated in patients who developed flap necrosis. N-butyl cyanoacrylate tissue adhesive was applied for gross thinning and penetrating keratoplasty (PK) was performed for advanced cases of keratitis. RESULTS: Mean patient age was 25.8 years (range: 18 to 44 years). Two patients had undergone unilateral surgery. Thirteen patients presented with infection in 1 eye and 2 patients had bilateral infection. The microorganisms isolated were filamentous fungi (4 eyes), Nocardia asteroides (5 eyes), atypical mycobacteria (4 eyes), Acanthamoeba (2 eyes), Corynebacterium (1 eye), and Staphylococcus epidermidis (1 eye). The infection resolved with medical treatment in 6 eyes, medical treatment and flap amputation in 4 eyes, and PK in 4 eyes. Two patients were lost to follow-up. Five eyes of 4 patients referred to us within 10 days of symptom onset resolved on medical treatment with final visual acuity ranging from 20/20 to 20/80. CONCLUSIONS: In a tropical region, it is important to consider uncommon organisms such as fungi, Nocardia, and Acanthamoeba as possible etiological agents in keratitis after LASIK. A detailed microbiology work-up will help in definitive diagnosis and appropriate treatment.

Design, synthesis and evaluation of (E)-alpha-benzylthio chalcones as novel inhibitors of BCR-ABL kinase.

Novel (E)-alpha-benzylthio chalcones are reported with preliminary in vitro activity data indicating that several of them are potent inhibitors (comparable to imatinib, the reference compound) of BCR-ABL phosphorylation in leukemic K562 cells, known to express high levels of BCR-ABL. The ability of such compounds to significantly inhibit K562 cell proliferation suggests that this scaffold could be a promising lead for the development of anticancer agents that are able to block BCR-ABL phosphorylation in leukemic cells.

Inferior rectus paresis and medial rectus overaction following retrobulbar anesthesia for cataract surgery.

Strabismus is a well recognized complication of retrobulbar anesthesia for cataract surgery. This may manifest as either paresis or sometimes contracture (overaction) in the late stage. Management of the patient is tailored to the individual case. Herein, we report a patient with inferior rectus paresis and medial rectus overaction after retrobulbar anesthesia. The presenting symptom was diplopia increasing on downgaze, which improved with medial rectus recession and plication of the inferior rectus.

Sensitivity and specificity of teachers for vision screening among primary school children in South India.

AIMS: This study aims to determine the sensitivity and specificity of vision screening by school teachers among primary school children. SETTINGS AND DESIGN: Prospective nonrandomized clinical trial. SUBJECTS AND METHODS: The study was carried in primary school children of Madurai, Tamil Nadu from April 2007 to October 2007. Sixty-five primary school teachers from 57 schools around Madurai, Tamil Nadu, India, underwent a half-day training programme at the hospital. Each teacher on return to the school screened around a hundred children using the tumbling E. All screened children were subsequently screened by a team from the hospital. The optometrists used tumbling E (Snellen's 20/30 and Early Treatment of Diabetic Retinopathy Study (ETDRS) 20/32) to check the vision of all children. Any child complaining of defective vision or noted to have defective vision on screening underwent a comprehensive ophthalmic evaluation. The sensitivity and specificity of teacher screening was assessed based on the data obtained. RESULTS: Screening was completed for 5150 children. The prevalence of vision <20/30 was 2.82%. Teacher screening was noted to have a sensitivity of 24.8% and a specificity of 98.65%. Tumbling E ETDRS screening by the optometrist had the highest sensitivity of 94.48% and specificity of 97.09%. CONCLUSIONS: Our study shows that vision screening by trained optometrists is a very useful tool to identify visual impairment in primary school children. Measures need to be taken to improve the sensitivity of teacher screening before recommending its generalized use.

Outcome of delayed adjustable strabismus surgery in children using a bow-tie optional adjustable technique.

PURPOSE: The aim of this article is to study the feasibility of a delayed adjustable technique of strabismus surgery in children using an optional adjustable suture technique. METHODS: The retrospective study included patients <12 years of age. Recessions were done using an optional adjustable bow-tie technique and resections were done by the conventional technique. Patients were evaluated on the third postoperative day and adjustments done when needed. Statistical analysis was done using Microsoft Excel 2010®. RESULTS: The study included 11 patients with exotropia and 16 patients with esotropia. The mean age of the patients was 5.2 years (range 1-11 years). The mean preoperative distance deviation was 46.7 ± 10.4 prism diopters (PD) for exotropic patients and 47.1 ± 16.9 PD for esotropic patients. The mean preoperative near deviation was 46.6 ± 11 PD for exotropic patients and 52.4 ± 17.1 PD for esotropia. Two patients with exotropia (18.2%) and four patients with esotropia (25%) were adjusted under intravenous ketamine in the operating room under anesthetist supervision. No difficulty was encountered in advancing/recessing the muscles. The success rate at 1 month was 100% for exotropia and 87.5% for esotropia. The success rate at the final follow-up was 81.8% for patients with exotropia and 68.7% for patients with esotropia. CONCLUSIONS: This delayed optional adjustable strabismus surgery technique provides good short-term results and lower adjustment rates.

Safety and efficacy of radial versus femoral access for rotational Atherectomy: A systematic review and meta-analysis.

INTRODUCTION: Over the recent years, there has been increased interest in the use of transradial (TR) access for percutaneous coronary intervention (PCI), including rotational atherectomy (RA). However, a large proportion of operators seem to be reluctant to use TR access for complex PCI including rotational atherectomy for heavily calcified coronary lesions. METHODS: We searched MEDLINE, ClinicalTrials.gov and the Cochrane Library for studies comparing radial versus femoral access in patients undergoing RA. Studies were included if they reported at least one of the following outcomes in each group separately: major adverse cardiac events (MACE), major bleeding, stent thrombosis, myocardial infarction (MI), hospital length of stay, radiation exposure, procedure time, procedure success and all-cause mortality. Odds ratio (OR) or mean difference (MD) with 95% confidence interval (CI) were calculated and a p-value of <0.05 was considered as a level of significance. RESULTS: This meta-analysis included 5 retrospective studies with 3315 patients undergoing RA via radial access and 5838 patients via femoral access. Radial access was associated with lower major access site bleeding (OR: 0.45, 95% CI: 0.31-0.67, p < 0.001), and radiation exposure (MD: -16.1, 95%CI: -25.4--6.7 Gy cm2, p = 0.0007). There were no significant differences observed in all-cause in-hospital mortality (OR: 0.92, 95% CI: 0.69-1.23, p = 0.58); MACE (OR: 0.80, CI: 0.63, 1.02, p = 0.08), stent thrombosis (OR: 0.28, 95%CI: 0.06-1.33 p = 0.11); and MI (OR: 0.43, 95%CI: 0.15-1.24, p = 0.12). There were no significant differences in hospital stay, procedure time or procedure success between the two groups (p > 0.05). CONCLUSION: This meta-analysis of 9153 patients from observational studies demonstrates similar all-cause mortality, MACE, procedural success and procedural time during RA performed using TR access and TF access. However, TR access was associated with decreased access site bleeding and radiation exposure. Given the observational nature of these findings, a randomized controlled trial is warranted for further evidence.

Design, synthesis, and biological evaluation of (E)-styrylbenzylsulfones as novel anticancer agents.

Cell cycle progression is regulated by cyclins and cyclin-dependent kinases, which are formed at specific stages of the cell cycle and regulate the G1/S and G2/M phase transitions, employing a series of "checkpoints" governed by phosphorylation of their substrates. Tumor development is associated with the loss of these checkpoint controls, and this provides an approach for the development of therapeutic agents that can specifically target tumor cells. Here, we describe the synthesis and SAR of a novel group of cytotoxic molecules that selectively induce growth arrest of normal cells in the G1 phase while inducing a mitotic arrest of tumor cells resulting in selective killing of tumor cell populations with little or no effect on normal cell viability. The broad spectrum of antitumor activity in vitro and xenograft models, lack of in vivo toxicity, and drug resistance suggest potential for use of these agents in cancer therapy.

Design, synthesis, and biological evaluation of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibitors.

A series of 20 novel 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were designed, synthesized, and screened in vitro for anti-inflammatory activity. These compounds were designed for evaluation as dual inhibitors of cyclooxygenases (COX-1 and COX-2) and lipoxygenases (LOX-5, LOX-12, and LOX-15) that are responsible for inflammation and pain. All pyrazoline molecules prepared are optically active and compounds that are more potent in COX-2 inhibitory activity (5a and 5f) were resolved by chiral column and each enantiomer was tested for cyclooxygenase inhibitory activity. Molecular modeling and comparison of molecular models of 5a enantiomers with that of celecoxib model shows that 5a (enantiomer-1) and 5a (enantiomer-2) have more hydrogen bonding interactions in the catalytic domain of COX-2 enzyme than celecoxib. Compounds 5a, 5e, and 5f showed moderate to good LOX-5 and LOX-15 inhibitory activity and this is comparable to that of celecoxib and more potent than rofecoxib.

Situational Restriction of Elevation in Adduction Relieved by Faden on the Medial Rectus.

We describe a patient with situational restriction of elevation in adduction in his left eye. Clinical examination pointed to instability of the left medial rectus pulley. This was corrected by Faden on the medial rectus. The importance of this relatively new concept in identifying and treating orbital pulley instability is discussed.