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Biomedical subjects

Steven D Schwartz

Publications and source records attributed to Steven D Schwartz.

At least 19 recordsLinked to original sources
PubMed2006

Outcomes of vitrectomy with inferior retinectomy in patients with recurrent rhegmatogenous retinal detachments and proliferative vitreoretinopathy.

PURPOSE: To report the anatomic and functional outcomes of patients treated with vitrectomy and inferior retinectomy for recurrent, rhegmatogenous retinal detachment complicated by proliferative vitreoretinopathy (PVR). DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: Fifty-six patients with recurrent, rhegmatogenous retinal detachments complicated by PVR who underwent an inferior retinectomy for repair. METHODS: Retrospective review over a 6-year period of patients treated with vitrectomy and inferior retinectomy. MAIN OUTCOME MEASURES: The primary outcome was anatomic success, defined as complete retinal reattachment. Secondary outcomes included change in visual acuity, the mean number of operations required for complete retinal reattachment, number of operations before retinectomy, use of silicone oil tamponade, location and extent of retinectomy, whether lensectomy was undertaken, and incidence of postoperative complications. RESULTS: Complete retinal reattachment was achieved in 52 of 56 patients (93%), with a mean follow-up of 25 months (range, 6-70 months). After retinal reattachment, visual acuity was improved or stabilized in 39 of 56 patients (70%). The mean number of operations for retinal detachment before diagnosis of PVR requiring retinectomy was 1.8 (range, 1-5). Patients undergoing radical anterior vitreous base dissection and lensectomy at the time of first retinectomy had a higher success rate than those who did not: 74% versus 38%, respectively (P = 0.011). Furthermore, tamponade with silicone oil had a higher success rate than tamponade with gas: 71% versus 18%, respectively (P = 0.002). Of the 56 patients, 9 (16%) had 1 or more of the following complications: keratopathy requiring penetrating keratoplasty (n = 4), glaucoma requiring aqueous shunt device (n = 3), and hypotony (n = 3). Silicone oil removal was performed in 26 of 45 patients (58%) before the last follow-up visit, with a 1 in 26 (4%) redetachment rate. CONCLUSIONS: When combined with anterior base dissection, inferior retinectomy may be useful in the surgical treatment of complex PVR-related retinal detachment. The authors show that with lensectomy, radical anterior base dissection, and inferior retinectomy, anatomic success rates are improved and visual function can be maintained. In addition, silicone oil offers an advantage over gas tamponade in these cases.

Aged↗
PubMed2006

Insight into catalytically relevant correlated motions in human purine nucleoside phosphorylase.

The catalytic site of the homotrimeric enzyme human purine nucleoside phosphorylase enzyme (hPNP) features residue F200 and the 241-265 loop directly skirting the purine base and a residue belonging to the adjacent monomer, F159, immediately conterminous to the ribosyl moiety. Crystallographic B-factors of apo human purine nucleoside phosphorylase, and hPNP complexed with substrate/transition state (TS) analogues, show that residue E250 is the centroid of a highly mobile loop region. Furthermore, superimposition of apo hPNP and hPNP complexed with TS analogue Immucillin-H shows a tightening of the active site, caused by the ligand-dependent 241-265 loop rearrangement taking place upon substrate/inhibitor binding, suggesting a putative dynamic role of the loop in binding/catalysis. However, crystallographic structures reveal only average atomic positions, and more detailed information is needed to discern the dynamic behavior of hPNP. The Essential Dynamics (ED) method is used here to investigate the existence of correlated motions in hPNP and consequently proposes mutagenesis assays to estimate the relative importance of these motions in the phosphorolytic efficiency of the reaction catalyzed by hPNP. We compare the concerted motions obtained from multiple molecular dynamics simulations of apo and Michaelis complex of hPNP both in vacuo and in solution. The results of the principal component analysis for the apo hPNP indicate the existence of strong correlations predominantly in the vicinity of residue F159. However, for the Michaelis complex, concerted motions are seen mostly around both active site residue F200 and loop residue E250. Additionally, for a simulation depicting the relaxation of tight complexed hPNP with a TS analogue, toward its relaxed apo form (after removal of the TS analog), a combination of the apo hPNP and Michaelis complex motions is found, with prominent concerted modes centered around neighboring residues F159, F200, and E250. Finally, we probed the extent to which these concerted motions bear an intrinsic catalytic role by performing experimental site-directed mutagenesis on some residues, followed by kinetic analysis. The F159G and F200G mutants displayed a strong increase in K(M) and modest decrease in k(cat), suggesting that these concerted motions may provide dynamical roles in substrate binding and/or catalysis. However, further structural data for the hPNP mutants are needed to confirm our hypothesis.

Binding Sites↗
PubMed2006

Severe steroid-induced glaucoma following intravitreal injection of triamcinolone acetonide.

PURPOSE: To report a case of severe corticosteroid-induced glaucoma after intravitreal injection of triamcinolone acetate in a 34-year-old man without a history of glaucoma. DESIGN: Observational case report. METHODS: Retrospective review of a clinical case. RESULTS: A 34-year-old man acquired visual field defects and severe vision loss in both eyes after intravitreal injection of triamcinolone for diabetic macular edema. CONCLUSIONS: Intravitreal injection of triamcinolone is a commonly performed treatment for many retinal conditions. This treatment has the potential to cause severe vision loss as a result of intractable corticosteroid-induced glaucoma.

Adult↗
PubMed2006

25-Gauge pars plicata vitrectomy for stage 4 and 5 retinopathy of prematurity.

PURPOSE: To describe the authors' technique and initial experience using the 25-gauge vitrectomy system for stage 4 and 5 tractional retinal detachment in retinopathy of prematurity (ROP). METHODS: Consecutive patients with stage 4 or 5 ROP treated with 25-gauge vitrectomy surgery between July 2003 and May 2004 were studied retrospectively. Eyes with prior vitrectomy surgery were excluded. A modified three-port 25-gauge approach was used in which conjunctival dissection and suturing of sclerotomies was necessary. The primary outcome was anatomic success defined as retinal reattachment. Secondary outcomes were intra- and postoperative complications. RESULTS: Fifteen eyes in 12 infants were identified that had 25-gauge vitrectomy for stage 4 or 5 ROP: 11/15 (73%) had stage 4A; 2/15 (13%), stage 4B; and 2/15 (13%), stage 5. All 15/15 (100%) were referred with incomplete anterior laser ablation of threshold ROP. Six of 15 (40%) required lensectomy at the time of initial pars plicata vitrectomy. Seven of 15 (47%) required more than one retinal surgery for persistent retinal detachment and/or vitreous hemorrhage. Eleven of 15 (73%) eyes had documented retinal reattachment after one or more surgeries at the last follow-up. Complications included vitreous hemorrhage (2) and postoperative cataract (1). CONCLUSIONS: Twenty-five gauge vitrectomy is a safe and effective treatment approach for tractional retinal detachments in stage 4 and 5 ROP. Complications may be comparable to vitrectomies performed with two-port 20-gauge vitrectomy. Modifications of the 25-gauge vitrectomy system included conjunctival dissection and suturing of conjunctiva and sclerotomies at the conclusion of the case.

Equipment Design↗
PubMed2005

Changes in the chemical and dynamic properties of cardiac troponin T cause discrete cardiomyopathies in transgenic mice.

Cardiac troponin T (cTnT) is a central component of the regulatory thin filament. Mutations in cTnT have been linked to severe forms of familial hypertrophic cardiomyopathy. A mutational "hotspot" that leads to distinct clinical phenotypes has been identified at codon 92. Although the basic functional and structural roles of cTnT in modulating contractility are relatively well understood, the mechanisms that link point mutations in cTnT to the development of this complex cardiomyopathy are unknown. To address this question, we have taken a highly interdisciplinary approach by first determining the effects of the residue 92 mutations on the molecular flexibility and stability of cTnT by means of molecular dynamics simulations. To test whether the predicted alterations in thin filament structure could lead to distinct cardiomyopathies in vivo, we developed transgenic mouse models expressing either the Arg-92-Trp or Arg-92-Leu cTnT proteins in the heart. Characterization of these models at the cellular and whole-heart levels has revealed mutation-specific early alterations in transcriptional activation that result in distinct pathways of ventricular remodeling and contractile performance. Thus, our computational and experimental results show that changes in thin filament structure caused by single amino acid substitutions lead to differences in the biophysical properties of cTnT and alter disease pathogenesis.

Analysis of Variance↗
PubMed2005

How enzyme dynamics helps catalyze a reaction in atomic detail: a transition path sampling study.

We have applied the Transition Path Sampling algorithm to the reaction catalyzed by the enzyme Lactate Dehydrogenase. This study demonstrates the ease of scaling Transition Path Sampling for applications on many degree of freedom systems, whose energy surface is a complex terrain of valleys and saddle points. As a Monte Carlo importance sampling method, transition path sampling is capable of surmounting barriers in path phase space and focuses simulation on the rare event of enzyme catalyzed atom transfers. Generation of the transition path ensemble, for this reaction, resolves a paradox in the literature in which some studies exposed the catalytic mechanism of hydride and proton transfer by lactate dehydrogenase to be concerted and others stepwise. Transition path sampling has confirmed both mechanisms as possible paths from reactants to products. With the objective to identify a generalized, reduced reaction coordinate, time series of both donor-acceptor distances and residue distances from the active site have been examined. During the transition from pyruvate to lactate, residues located behind the transferring hydride collectively compress toward the active site causing residues located behind the hydride acceptor to relax away. It is demonstrated that an incomplete compression/relaxation transition across the donor-acceptor axis compromises the reaction.

Catalysis↗
PubMed2005

Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration.

PURPOSE: To investigate the maximum tolerated dose of ranibizumab administered as a single intravitreal injection. DESIGN: Open-label, 5-center, uncontrolled, prospective, dose-ranging, interventional case series. PARTICIPANTS: Twenty-seven patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) with best-corrected Snellen equivalent visual acuity (VA) of 20/100 or worse and considered ineligible for laser photocoagulation or photodynamic therapy. METHODS: A single intravitreal injection of ranibizumab was to be administered at 1 of 6 escalating doses (50, 150, 300, 500, 1000, and 2000 microg), with escalation to the next dose level occurring only after the safety and tolerability of the lower dose level was established through postinjection day 14. Follow-up examinations were performed on postinjection days 1, 3, 7, 14, 42, and 90. Enrollment was stopped if > or =2 patients experienced dose-limiting toxicity. MAIN OUTCOME MEASURES: The primary safety measures were changes from baseline in VA, intraocular pressure (IOP), intraocular inflammation, and production of antiranibizumab antibody. Dose-limiting toxicity was defined by intraocular inflammation, elevated IOP, reduced VA, or hemorrhage within 90 days after injection. RESULTS: All patients completed this single intravitreal injection study, and 500 microg of ranibizumab was the maximum tolerated dose. At the higher dose of 1000 microg, significant intraocular inflammation was noted. All adverse events were self-limited, and no infectious endophthalmitis occurred. Aqueous or vitreous ocular inflammation occurred in 12 subjects, with complete resolution within 42 days. In 9 of the subjects, the inflammation was graded as trace to 1+ and required no treatment; in 3 of the subjects, the inflammation was graded as 2+ or 3+, and 2 of the 3 were treated with topical 1% prednisolone acetate. No serum antiranibizumab antibodies were detected. All patients had VA similar or improved compared with baseline values. CONCLUSION: The maximum tolerated single dose of ranibizumab in neovascular AMD patients was 500 microg. Single intravitreal injections of ranibizumab up to a dose of 500 microg were safe and well tolerated in this small group of patients.

Aged↗
PubMed2005

A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema.

OBJECTIVE: To evaluate the safety and efficacy of pegaptanib sodium injection (pegaptanib) in the treatment of diabetic macular edema (DME). DESIGN: Randomized, double-masked, multicenter, dose-ranging, controlled trial. PARTICIPANTS: Individuals with a best-corrected visual acuity (VA) between 20/50 and 20/320 in the study eye and DME involving the center of the macula for whom the investigator judged photocoagulation could be safely withheld for 16 weeks. INTERVENTION: Intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections at study entry, week 6, and week 12 with additional injections and/or focal photocoagulation as needed for another 18 weeks. Final assessments were conducted at week 36. MAIN OUTCOME MEASURES: Best-corrected VA, central retinal thickness at the center point of the central subfield as assessed by optical coherence tomography measurement, and additional therapy with photocoagulation between weeks 12 and 36. RESULTS: One hundred seventy-two patients appeared balanced for baseline demographic and ocular characteristics. Median VA was better at week 36 with 0.3 mg (20/50), as compared with sham (20/63) (P = 0.04). A larger proportion of those receiving 0.3 mg gained VAs of > or =10 letters (approximately 2 lines) (34% vs. 10%, P = 0.003) and > or =15 letters (18% vs. 7%, P = 0.12). Mean central retinal thickness decreased by 68 microm with 0.3 mg, versus an increase of 4 microm with sham (P = 0.02). Larger proportions of those receiving 0.3 mg had an absolute decrease of both > or =100 microm (42% vs. 16%, P = 0.02) and > or =75 microm (49% vs. 19%, P = 0.008). Photocoagulation was deemed necessary in fewer subjects in each pegaptanib arm (0.3 mg vs. sham, 25% vs. 48%; P = 0.04). All pegaptanib doses were well tolerated. Endophthalmitis occurred in 1 of 652 injections (0.15%/injection; i.e., 1/130 [0.8%] pegaptanib subjects) and was not associated with severe visual loss. CONCLUSIONS: In this phase II trial, subjects assigned to pegaptanib had better VA outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation at follow-up.

Adult↗
PubMed2004

Promoting vibrations in human purine nucleoside phosphorylase. A molecular dynamics and hybrid quantum mechanical/molecular mechanical study.

Crystallographic studies of human purine nucleoside phosphorylase (hPNP) with several transition-state (TS) analogues in the immucillin family showed an unusual geometric arrangement of the atoms O-5', O-4', and O(P), the nucleophilic phosphate oxygen, lying in a close three-oxygen stack. These observations were corroborated by extensive experimental kinetic isotope effect analysis. We propose that protein-facilitated dynamic modes in hPNP cause this stack, centered on the ribosyl O-4' oxygen, to squeeze together and push electrons toward the purine ring, stabilizing the oxacarbenium character of the TS. As the N-ribosidic bond is cleaved during the reaction, the pK(a) values of N-7 and O-6 increase by the electron density expelled by the oxygen-stack compression toward the purine ring. Increased electron density in the purine ring improves electrostatic interactions with nearby residues and facilitates the abstraction of a proton from a solvent proton or an unidentified general acid, making the purine a better leaving group, and accelerating catalysis. Classical and mixed quantum/classical molecular dynamics (MD) simulations of the Michaelis complex of hPNP with the substrates guanosine and phosphate were performed to assess the existence of protein-promoting vibrations (PPVs). Analogous simulations were performed for the substrates in aqueous solution. In the catalytic site, the O-5', O-4', and O(P) oxygens vibrate at frequencies of ca. 125 and 465 cm(-1), as opposed to 285 cm(-1) in the absence of hPNP. The hybrid quantum mechanical/molecular mechanical method was used to assess whether this enzymatic vibration pushing the oxygens together is coupled to the reaction coordinate, and thus has a direct positive impact on catalysis. The potential energy surface for the phosphorolysis reaction for several snapshots taken from the classical MD simulation showed substantial differences in oxygen compression. Our calculations showed the existence of PPVs coupled to the reaction coordinate, which effect electronic alterations in the active site by pushing the three oxygen centers together in proximity, and accelerate substrate turnover in the phosphorolysis reaction catalyzed by hPNP.

Animals↗
PubMed2004

Transition path sampling study of classical rate-promoting vibrations.

It is now widely accepted that there is a class of enzymatic proton transfer reactions, which proceed through quantum tunneling. In a series of papers we have argued that some experimental features of these reactions can be explained by assuming the presence of a "rate-promoting" vibration which brings donor and acceptor closer together, thus leading to rate enhancement. There has never been a study of this effect for classical systems. We used transition path sampling to study the equivalent classical problem and found a complicated dynamical behavior that cannot be captured by transition state theory. Slow promoting vibrations lead to reactive trajectories that overshoot the saddle point, but on the other hand the short period of fast oscillations allows the reactants to stay only briefly in a low-barrier regime. There is a competition between these effects, which results to an intermediate value for the frequency of the rate-promoting vibration that is optimal for enhancing the rate.

Algorithms↗
PubMed2004

Rate-promoting vibrations and coupled hydrogen-electron transfer reactions in the condensed phase: a model for enzymatic catalysis.

A model is presented for coupled hydrogen-electron transfer reactions in condensed phase in the presence of a rate promoting vibration. Large kinetic isotope effects (KIEs) are found when the hydrogen is substituted with deuterium. While these KIEs are essentially temperature independent, reaction rates do exhibit temperature dependence. These findings agree with recent experimental data for various enzyme-catalyzed reactions, such as the amine dehydrogenases and soybean lipoxygenase. Consistent with earlier results, turning off the promoting vibration results in an increased KIE. Increasing the barrier height increases the KIE, while increasing the rate of electron transfer decreases it. These results are discussed in light of other views of vibrationally enhanced tunneling in enzymes.

Journal Article↗
PubMed2004

The fellow eye of patients with rhegmatogenous retinal detachment.

OBJECTIVE: To determine how often the fellow eyes of patients with rhegmatogenous retinal detachment (RRD) without proliferative vitreoretinopathy (PVR) harbor vision-threatening conditions at presentation and during follow-up. DESIGN: Retrospective, observational case series. PARTICIPANTS: Two hundred forty-eight patients with RRD without PVR were studied. INTERVENTION: The authors observed the fellow eye of patients with RRD for vision-threatening pathology. MAIN OUTCOME MEASURE: Detection of vision-threatening pathology in the fellow eye of patients with RRD without PVR. RESULTS: Two hundred forty-eight patients were observed for an average of 5.2 years. One hundred fifty-seven vision-threatening events or diagnoses occurred in the fellow eye, including pre-existing and newly diagnosed conditions, 97 (62%) of which were rhegmatogenous in nature. Fifty-six patients (23%) had retinal detachments in their fellow eye, including those with a history of RRD repair (28 eyes), those presenting with bilateral RRD (4 eyes), and those developing new RRD during follow-up (24 eyes). In addition, 1 patient developed recurrent retinal detachment in the fellow eye during follow-up. Retinal tears were diagnosed and treated with laser retinopexy or cryotherapy in 30 (12%) fellow eyes (4 before the initial examination, 7 upon initial examination, and 19 on follow-up). Lattice degeneration was present in 27 (11%) fellow eyes. CONCLUSIONS: Patients who develop RRD are at considerable risk for developing vision-threatening events, particularly rhegmatogenous events, in the fellow eye.

Adolescent↗
PubMed2004

Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: ophthalmic findings: SST report no. 11.

PURPOSE: To present visual acuity (VA) and related findings from patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of subfoveal choroidal neovascularization secondary to age-related macular degeneration (SST Group N Trial). DESIGN: Randomized clinical trial. PARTICIPANTS: Eligible patients had age-related macular degeneration with subfoveal choroidal neovascularization, some with a classic pattern on fluorescein angiography, and best-corrected VA (BCVA) of 20/100 to 20/800 in one eye (study eye) that had received no treatment in the macula. Any contiguous blood had to account for <50% of the total area occupied by the subfoveal lesion (maximum size, 9.0 disc areas [22.9 mm2]). METHODS: Randomization was stratified by VA and by clinical center. All patients were scheduled for study examinations at 3, 6, 12, and 24 months after enrollment for assessment of study outcomes. MAIN OUTCOME MEASURE: A successful outcome was defined a priori to be either improvement of BCVA or VA no more than 1 line (7 letters) worse than baseline at the 24-month examination. RESULTS: Of 454 patients enrolled, 228 study eyes were assigned to observation and 226 to surgery. The percentages of eyes that had successful outcomes were similar in the 2 arms: 44% assigned to observation and 41% assigned to surgery. Median VA losses from baseline to the 24-month examination were 2.1 lines (10.5 letters) in the observation arm and 2.0 lines (10 letters) in the surgery arm. Median VA declined from 20/100 at baseline to 20/400 at 24 months in both arms. No subgroup of patients was identified in which submacular surgery led to better VA outcomes. In the surgery arm, 55 (39%) of 142 initially phakic eyes had cataract surgery by the 24-month examination, compared with 6 (5%) of 133 eyes in the observation arm. Rhegmatogenous retinal detachment occurred in 12 surgery eyes (5%) and 1 observation eye. CONCLUSIONS: Submacular surgery, as performed in this clinical trial, did not improve or preserve VA for 24 months in more eyes than observation and is not recommended for patients with similar lesions. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Aged↗
PubMed2003

Bilateral choroidal folds and optic neuropathy: a variant of the crowded disk syndrome?

PURPOSE: To describe the clinical features of the syndrome that includes bilateral choroidal folds and optic neuropathy and to propose a novel etiology to explain this presentation. DESIGN: Observational small case series. PARTICIPANTS: Three patients. METHODS: Three patients received an extensive clinical work-up including complete ocular examination, A and B scan ultrasonography, Humphrey visual field analysis, and imaging of the brain and orbit. Neurological consultation was obtained in each patient two of whom underwent lumbar puncture. The findings of this detailed investigation are reported. RESULTS: Each patient demonstrated bilateral choroidal folds with optic disk congestion and leakage in one eye and optic atrophy in the fellow eye. Extensive ocular and extraocular investigation failed to uncover a specific etiology. Pseudotumor cerebri, a well-documented cause of papilledema and choroidal folds, was ruled out in each case. Each patient did demonstrate variable degrees of hyperopia and shortened axial lengths. CONCLUSIONS: The syndrome of bilateral choroidal folds and optic neuropathy may have various etiologies. Pseudotumor cerebri needs to be definitively ruled out. Normal neuro-ophthalmological investigation including lumbar puncture may indicate an alternative cause. Idiopathic acquired hyperopia in middle-aged patients who are hyperopic with shortened axial lengths may be associated with choroidal folds and a constricted scleral canal causing optic disk congestion and complicated by nonarteritic anterior ischemic optic neuropathy due to a crowded disk.

Aged↗
PubMed2002

Identification of a protein-promoting vibration in the reaction catalyzed by horse liver alcohol dehydrogenase.

In this article we present computational studies of horse liver alcohol dehydrogenase (HLADH). The computations identify a rate-promoting vibration that is symmetrically coupled to the reaction coordinate. In HLADH a bulky amino acid (Val203) is positioned at the face of the nicotinamide adenine dinucleotide (NAD(+)) cofactor distal to alcohol substrate to restrict the separation of reactants and control the stereochemistry. Molecular dynamics simulations were performed on the dimeric HLADH, including the NAD cofactor, the substrate, and the crystallographic waters, for three different configurations, reactants, products, and transition state. From the spectral density for the substrate-NAD relative motion, and that for the NAD-Val203 relative motion, we find that the two motions are in resonance. By computing the associated spectrum, we find that the reaction coordinate is coupled with the substrate-NAD motion, and from the fact that the coupling vanishes at or near the transition state (demonstrated by the disappearance of strong features in the spectral density), we conclude that the substrate-NAD motion plays the role of a promoting vibration symmetrically coupled to the reaction coordinate.

Alcohol Dehydrogenase↗