Optic Disc Pit with Peripapillary Retinoschisis Presenting as a Localized Retinal Nerve Fiber Layer Defect

A 59-year-old woman was referred to our clinic for a glaucoma evaluation. The visual acuity and intraocular pressure were normal in both eyes. However, red-free fundus photography in the left eye showed a superotemporal wedge-shaped retinal nerve fiber layer defect, and visual field testing showed a corresponding partial arcuate scotoma. In an optical coherence tomography examination, the macula was flat, but an arcuate-shaped peripapillary retinoschisis was found. Further, the retinoschisis seemed to be connected with a superotemporal optic pit shown in a disc photograph. After 3 months of a topical prostaglandin analogue medication, the intraocular pressure in the retinoschisis eye was lowered from 14 to 10 mmHg and the peripapillary retinoschisis was almost resolved. We report a rare case of an optic disc pit with peripapillary retinoschisis presenting as a localized retinal nerve fiber layer defect

Development and Application of a Novel Enhanced Sampling Method and Bayesian Analysis for Characterizing Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) are a class of proteins with wide-rangingsignificance in signaling and disease that do not adopt a dominant folded structure asmonomers. Rather, the structures of IDPs in solution are best described as ensembles ofconformational states that may range from being fully random coil to partially ordered.This structural plasticity of IDPs is theorized to facilitate regulation of their interactionwith other species, as in signal transduction or aggregation of IDPs into ordered fibrils.Characterizing the structural ensembles of IDPs in the free, solvated state is key tounderstanding the mechanisms of these interactions, and correspondingly the role an IDPspecies plays in signaling or disease.The rapid interconversion between conformational states, however, complicates theexperimental study of IDPs because most experimental signals report highly averagedinformation. Computational modeling with validation through comparison to experimenthas therefore been a main approach to characterizing IDP structure and dynamics. Thefocus of my dissertation is on the development of new methods for computational study ofIDPs, facilitating better and less expensive de novo generation of IDP structural ensemblesand improving the metrics used to evaluate the degree of agreement between a simulatedensemble and a set of experimental data.Despite vast improvements in computational power and efficiency, moleculardynamics (MD) simulations of IDPs for generating conformational ensembles are stilllimited by the expense of calculations. In Chapter 2 I present the development of a newenhanced sampling method – temperature cool walking (TCW) – and comparison of itsperformance against a standard method – temperature replica exchange (TREx). The TCWmethod accelerates the rate of convergence to the equilibrium conformational ensemblewith increased sampling acceleration relative to TREx at greatly reduced computationalcost.The second major limitation in MD is the accuracy of the force field. Most classicalfixed charge force fields were parameterized using data from folded proteins, and havebeen thought to be biased to overly collapsed and structured conformations. This hasmotivated the development of IDP-tailored force fields that sample greater disorder, at thepotential expense of the ability to model stabilizing interactions between an IDP and itsbinding partners. In Chapter 3, I assess to what degree the shortcomings assigned tostandard force fields may be due to insufficient sampling by characterizing theperformance of standard and newly modified force fields on the Alzheimer’s peptideamyloid-β using both TREx and TCW. We find that with improved sampling, standard andmodified force fields produce similar structural ensembles, suggesting that both areappropriate for simulation of the disordered state. In Chapter 4 I present preliminaryresults building off of this work by characterizing the performance of a polarizable forcefield modeling a synthetic peptide that demonstrates complete loss of helical content withincreasing temperature. Inclusion of polarization effects has been thought to be key foraccurate modeling of such multicomponent systems, especially when there is a shift in theelectrostatic environment as is the case for the unfolding peptide. Our early results, whilelimited by current lack of convergence for tests using the polarizable force field andneeding further confirmation, match that expectation by finding early evidence of greaterresponse to temperature by the polarizable force field than fixed charge comparators.The last work presented here is in the development of new methods for calculatingthe degree of agreement between a simulated IDP ensemble and experimental data. Backcalculationof experimental data from structure can be very imprecise, motivating thedevelopment in Chapter 5 of scoring formalisms that account for variable uncertainties inboth back-calculation and experiment for diverse experimental data types. In summary, themethods described in this dissertation seek to improve computational study of IDPs byfacilitating better, less expensive generation of IDP ensembles and producing moreinformative metrics for evaluating their agreement with experiment

Abrupt vessel closure complicating coronary angioplasty: Clinical, angiographic and therapeutic profile

AbstractTo assess the clinical, angiographic and procedural correlates of outcome after abrupt vessel closure during coronary angioplasty, results were analyzed of 109 patients (8.3%) who had abrupt vessel closure during 1,319 consecutive coronary angioplasty procedures performed between July 1, 1988 and June 30, 1990. These 109 patients had a mean age of 59 ± 11 years; 63% were male, 57% had had a prior myocardial infarction and 61% had multivessel disease. Coronary angioplasty was performed in the settings of acute myocardial infarction (14%), recent myocardial infarction (36%), unstable angina (34%) and stable ischemia (29%).Abrupt vessel closure occurred at a median of 27 min (range 0 min to 5 days) from the first balloon inflation. By angiographic criteria, thrombus or coronary dissection was identified in 20% and 28% of cases, respectively; both thrombus and dissection were present in 7% of closures, and 45% were due to indeterminate mechanisms. Successful reversal of abrupt vessel closure, defined as restoration of normal Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow without resultant Q wave myocardial infarction, emergency bypass surgery or death, was achieved in 47 patients (43%). By hierarchal analysis, the incidence of death, emergency coronary bypass surgery, Q wave and non-Q wave myocardial infarction was 8%, 20%, 9% and 11%, respectively.Univariate analysis using 23 clinical, morphologic and procedural variables demonstrated that successful outcome after abrupt closure was associated with prolonged balloon inflations (>120 s) (odds ratio = 6.87, p < 0.001), unstable angina (odds ratio = 2.37, p = 0.034) and placement of an intracoronary stent (odds ratio = 5.33, p = 0.062). By multivariate analysis, independent correlates of successful outcome were prolonged balloon inflations (odds ratio = 5.11, p = 0.001) and intracoronary stenting (odds ratio = 4.37, p = 0.049).Thus, although prolonged balloon inflations and intracoronary stents may improve outcome after abrupt vessel closure, the cumulative risk of morbidity or mortality remains significant and mandates investigation into improved strategies for its prevention and treatment

Abciximab reduces mortality in diabetics following percutaneous coronary intervention

AbstractOBJECTIVESWe sought to determine whether abciximab therapy at the time of percutaneous coronary intervention (PCI) would favorably affect one-year mortality in patients with diabetes.BACKGROUNDDiabetics are known to have increased late mortality following PCI.METHODSData from three placebo-controlled trials of PCI, EPIC, EPILOG, and EPISTENT, were pooled. The one-year mortality rate for patients with a clinical diagnosis of diabetes mellitus was compared with the rate for nondiabetic patients treated with either abciximab or placebo.RESULTSIn the 1,462 diabetic patients, abciximab decreased the mortality from 4.5% to 2.5%, p = 0.031, and in the 5,072 nondiabetic patients, from 2.6% to 1.9%, p = 0.099. In patients with the clinical syndrome of insulin resistance—defined as diabetes, hypertension, and obesity—mortality was reduced by abciximab treatment from 5.1% to 2.3%, p = 0.044. The beneficial reduction in mortality with abciximab use in diabetics classified as insulin-requiring was from 8.1% to 4.2%, p = 0.073. Mortality in diabetics who underwent multivessel intervention was reduced from 7.7% to 0.9% with use of abciximab, p = 0.018. In a Cox proportional hazards survival model, the risk ratio for mortality with abciximab use compared with placebo was 0.642 (95% confidence interval 0.458–0.900, p = 0.010).CONCLUSIONSAbciximab decreases the mortality of diabetic patients to the level of placebo-treated nondiabetic patients. This beneficial effect is noteworthy in those diabetic patients who are also hypertensive and obese and in diabetics undergoing multivessel intervention. Besides its potential role in reducing repeat intervention for stented diabetic patients, abciximab therapy should be strongly considered in diabetic patients undergoing PCI to improve their survival

Configurational Entropy of Folded Proteins and its Importance for Intrinsically Disordered Proteins

Many pairwise additive force fields are in active use for intrinsically disordered proteins (IDPs) and regions (IDRs), some of which modify energetic terms to improve description of IDPs/IDRs, but are largely in disagreement with solution experiments for the disordered states. We have evaluated representative pairwise and many-body protein and water force fields against experimental data on representative IDPs and IDRs, a peptide that undergoes a disorder-to-order transition, and for seven globular proteins ranging in size from 130-266 amino acids. We find that force fields with the largest statistical fluctuations consistent with the radius of gyration and universal Lindemann values for folded states simultaneously better describe IDPs and IDRs and disorder to order transitions. Hence the crux of what a force field should exhibit to well describe IDRs/IDPs is not just the balance between protein and water energetics, but the balance between energetic effects and configurational entropy of folded states of globular proteins