The Frontier stent registry: safety and feasibility of a novel dedicated stent for the treatment of bifurcation coronary artery lesions.

OBJECTIVES: The goal of this study was to evaluate the safety and performance of the Multi-Link Frontier coronary bifurcation stent system (Guidant Corp., Santa Clara, California), a novel dedicated device designed for permanent side branch (SB) access, stent delivery by simultaneous kissing balloon inflation, and optimal main branch (MB) and SB ostium scaffolding. BACKGROUND: The treatment of coronary bifurcation lesions remains challenging, and various approaches using stents have been proposed. METHODS: The primary end point was the 180-day incidence of major adverse cardiac events (MACE) per intent-to-treat analysis. Secondary end points included device success, 30-day MACE, angiographic restenosis, and target lesion revascularization (TLR) rates at 180 days. RESULTS: After a learning phase of two cases per center, 105 patients were prospectively included in 11 centers. The left anterior descending coronary artery/diagonal bifurcation was the target in 80% of cases. The Frontier stent was successfully implanted in 96 patients (91%), and procedural success was obtained in 93%. Two patients suffered in-hospital myocardial infarction (MI) secondary to SB occlusion, and one patient underwent elective coronary artery bypass grafting. At 30 days and 6 months, the MACE rates were 2.9% and 17.1% (no death, no subacute stent thrombosis, Q-wave MI 1.0% and 1.9%, non-Q-wave MI 1.0% and 1.9%, TLR 1.0% and 13.3%). The MB in-stent restenosis was 25.3%, in-segment 29.9%. The SB restenosis was 29.1%. The overall restenosis rate for any branch was 44.8%. CONCLUSIONS: The results of this Frontier registry demonstrate the safety and performance of this dedicated stent system for the treatment of bifurcation lesions. The device can be successfully implanted in more than 90% of all cases, with a high procedural success rate and low 30-day and 6-month MACE rates.

Renal function and long term mortality after unstable angina/non-ST segment elevation myocardial infarction treated very early and predominantly with percutaneous coronary intervention.

OBJECTIVES: To quantify the impact of baseline renal function on in-hospital and long term mortality in patients with unstable angina/non-ST elevation acute myocardial infarction (UA/NSTEMI) treated with a very early invasive strategy. DESIGN: Prospective cohort study of 1400 consecutive patients with UA/NSTEMI undergoing coronary angiography and subsequent coronary stenting of the culprit lesion as the primary revascularisation strategy within 24 hours of admission. Patients were stratified according to calculated glomerular filtration rate (GFR) on admission. RESULTS: In-hospital mortality was 0% among patients with a GFR > or = 130 ml/min/1.73 m2, 0.4% with a GFR of 90-129 ml/min/1.73 m2, 2.6% with a GFR of 60-89 ml/min/1.73m2, and 5.1% with a GFR of < 60 ml/min/1.73 m2. Cumulative three year survival rates were 92.6%, 95.5%, 91.9%, and 76.8%, respectively. Patients with a GFR of < 60 ml/min/1.73 m2 were four times more likely to die in hospital (hazard ratio (HR) 4.0, 95% confidence interval (CI) 1.8 to 9.1; p = 0.001) and four times more likely to die during long term follow up (HR 4.0, 95% CI 2.5 to 6.4; p < 0.001). After adjusting for potential confounders, a GFR of < 60 ml/min/1.73 m2 remained a strong independent predictor of long term mortality (HR 2.6, 95% CI 1.5 to 4.5; p = 0.001). CONCLUSIONS: Baseline renal function is a strong independent predictor of in-hospital and long term mortality after UA/NSTEMI treated with very early revascularisation.

Microcontact printing of proteins on oxygen plasma-activated poly(methyl methacrylate).

This paper describes a method for microcontact printing protein solutions onto polymer substrates temporarily activated by oxygen plasma. Following plasma treatment, poly(dimethyl siloxane) (PDMS) stamps were coated with an aqueous laminin solution then placed in direct contact with plasma-treated poly(methyl methacrylate) (PMMA) substrates. This process resulted in well defined laminin stripes on the PMMA surface when printing was performed within 45min of the plasma treatment. Axonal outgrowth from embryonic chick dorsal root ganglia (DRG) was largely confined to the stamped pattern, while over 90% of primary rat Schwann cells adhered to the protein stamped areas on the PMMA substrates. Oxygen-plasma treatment of the PMMA surface was necessary to deposit proteins that direct axonal outgrowth from chick DRG and Schwann cell adherence.

White blood cell count and long term mortality after non-ST elevation acute coronary syndrome treated with very early revascularisation.

OBJECTIVE: To evaluate the predictive value of white blood cell count (WBC) for short and long term mortality in patients with non-ST elevation acute coronary syndromes (NSTACS) treated with a very early invasive strategy. DESIGN: Prospective cohort study in 1391 consecutive patients with NSTACS undergoing very early revascularisation. Patients were stratified according to quartiles of WBC determined on admission. RESULTS: Kaplan-Meier survival analysis showed a cumulative three year survival of 93.8% in the first quartile of WBC (< 6800/mm(3)), 94.4% in the second quartile (6800-8000/mm(3)), 95.1% in the third quartile (8000-10000/mm(3)), and 82.4% in the fourth quartile (> 10000/mm(3)) at 36 months (p < 0.001 by log rank). Relative to patients in the three lower WBC quartiles, patients in the highest quartile were three times more likely to die during the hospitalisation (hazard ratio 3.2, 95% confidence interval (CI) 1.5 to 7.1; p = 0.003) and during long term follow up (hazard ratio 3.4, 95% CI 2.2 to 5.3; p < 0.001). By multivariate Cox regression analysis including baseline demographic, clinical, and angiographic covariables, WBC in the highest quartile remained a strong independent predictor of mortality (hazard ratio 3.3, 95% CI 1.9 to 5.6; p < 0.001). CONCLUSIONS: WBC is a strong independent predictor of short and long term mortality after NSTACS treated with very early revascularisation.

Schwann cell response to micropatterned laminin surfaces.

In the peripheral nervous system, Schwann cells are closely associated with, and play key roles in, the development, maintenance, and regeneration of peripheral neurons. Following injury, Schwann cell orientation may also play a role in guiding regenerating axons. To aid in the investigation of these interactions between Schwann cells and growing neurites, we have developed a method of controlling Schwann cell placement and orientation in vitro by using microlithographically patterned laminin substrates, alternating 20-microm regions of laminin with bovine serum albumin (BSA) stripes. The Schwann cells predominantly attached and elongated on the laminin stripes and organized into multicellular aggregates that were oriented with the micropattern. A detailed analysis of Schwann cell aggregate orientation and shape demonstrated a strong dependence on time. At 1 h after seeding the cells, 70% of the aggregates were oriented with respect to the micropattern; 94% were oriented at 24 h. Variations in laminin concentration and seeding density were also investigated. The only significant differences in Schwann cell response occurred 1 h after seeding (the earliest time point the cultures were observed), and the main factor controlling the cellular orientation appeared to be the presence of the laminin-BSA interface. This ability to control cell orientation and placement provides a tool for future investigations of Schwann cell-neuronal interactions in vitro.

Transpupillary thermotherapy as primary treatment for small choroidal melanomas.

OBJECTIVE: To report the short-term follow-up results of eyes containing small choroidal melanomas that were treated with transpupillary thermotherapy. METHODS: Twenty eyes with suspected small choroidal melanomas were treated with transpupillary thermotherapy using infrared light delivered from the diode laser. RESULTS: The age of the patients ranged from 26 to 82 years. In 14 patients, there was documented growth of the melanoma before transpupillary thermotherapy. The tumor thickness ranged from less than 1.0 to 3.2 mm. Seven tumors were treated more than once. Follow-up ranged from 6 months to more than 3 years. Following treatment, the tumor thickness decreased in all cases, usually within 2 months. Progressive atrophy of tumor mass and loss of pigmentation within the tumor continued beyond 1 year of follow-up in some eyes. Complications included field defects, vascular changes, and macular abnormalities. CONCLUSIONS: Transpupillary thermotherapy of small choroidal melanomas is usually followed by early tumor shrinkage but is complicated by dense scotomas, nerve fiber bundle defects, and, occasionally, macular abnormalities. The short-term follow-up results suggest that transpupillary thermotherapy may arrest the growth of selected small melanomas.

Transpupillary thermotherapy as primary treatment for small choroidal melanomas.

PURPOSE: To report short-term follow-up of eyes containing small choroidal melanomas that were treated with transpupillary thermotherapy (TTT). METHODS: Twenty eyes with suspected small choroidal melanomas were treated with TTT using infrared light delivered from the diode laser. RESULTS: The age of patients ranged from 26 to 82 years. In 14, there was documented growth of the melanoma prior to TTT. Tumor thicknesses ranged from less than 1 to 3.2 mm. Seven tumors were treated more than once. Follow-up ranged from 6 months to more than 3 years. Following treatment, tumor thicknesses decreased in all cases, usually within 2 months. Progressive atrophy of tumor mass and loss of pigmentation within the tumor continued beyond 1 year of follow-up in some eyes. Complications included field defects, vascular changes, and macular abnormalities. CONCLUSIONS: Transpupillary thermotherapy of small choroidal melanomas is usually followed by early tumor shrinkage but is complicated by dense scotomas, nerve fiber bundle defects, and occasionally macular abnormalities. Short-term follow-up suggests that TTT may arrest growth of selected small melanomas.

Methods for the study of nerve cell migration and patterning.

Recent advances in our ability to microfabricate tissue culture environments (1), and to store and retrieve microscopy data in a digital format, have made it increasingly possible to study fundamental aspects of neuronal migration and response to environmental cues. Neuronal migration refers to the migration of the growth cone at the tip of an extending neurite, a process that guides the neurite to its destination during neural development and regeneration (2). This chapter describes techniques for the observation of neuronal migration on both plain and patterned surfaces through the use of high-resolution, phase-contrast videomicroscopy. These techniques are particularly appropriate for analyzing the dynamics of single growth cone behavior in the presence of two-dimensional environmental microfeatures similar in scale to the growth cone dimensions (1-50 µm). Growth cone response to topographical features (3) or other three-dimensional environments are beyond the scope of this chapter. Substrate preparation procedures are derived from microlithography techniques first used in the microelectronics industry and adapted to cell culture systems (4-7). Glass cover slips are used as the substrate support to provide the required optical clarity for high-resolution microscopy, and patterns are created using laminin or collagen.

Nocardia choroidal abscess in a patient with systemic lupus erythematosus.

PURPOSE: Nocardia asteroides, a respiratory saprophyte in humans, may cause localized infection of the lungs in debilitated or immunosuppressed individuals. Haematogenous spread to the eye via the choroidal circulation may result in choroidal abscess formation. METHOD: We report the development of a choroidal abscess in the left eye of a woman treated with steroids and cyclophosphamide for systemic lupus erythematosus. Haematogenous spread of N. asteroides from a localized infection of the lung (empyema) is thought to have been the cause of the choroidal abscess. RESULTS: Surgical drainage of the empyema combined with intravenously administered antibiotics resulted in resolution of the choroidal abscess and improvement of vision. CONCLUSIONS: A choroidal abscess, caused by haematogenous spread of N. asteroides, may respond to appropriate systemic antibiotic treatment alone and not require ocular treatment.

Autocorrelation function and power spectrum of two-state random processes used in neurite guidance.

During development neurons extend and retract cytoskeletal structures, chiefly microtubules and filopodia, to process informational cues from the extracellular environment and thereby guide growth cone migration toward an appropriate synaptic partner. This cytoskeleton-based exploration is achieved by stochastic switching, with microtubules and filopodia alternating between growing and shortening phases apparently at random. If stabilizing signals are not detected during the growth phase, then the structures switch to a shortening state, from which they can again return to a growth phase, and so forth. A useful means of characterizing these stochastic processes in a model-independent way is by autocorrelation and spectral analysis. Previously, we compared experiment to theory by performing Monte Carlo simulations and computing the autocorrelation function and power spectrum from the simulated dynamics, an approach that is computationally intensive and requires recalculation whenever model parameters are changed. Here we present analytical expressions for the autocorrelation function and power spectrum, which compactly characterize microtubule and filopodial dynamics based on the stochastic, two-state model. The model assumes that the phase times are of variable duration and gamma-distributed, consistent with experimental evidence for microtubules assembled in vitro from purified tubulin. The analytical expressions permit the precise quantitative characterization of changes in microtubule and filopodial searching behavior corresponding to changes in the shape of the gamma distribution.

Neurite outgrowth and growth cone morphology on micropatterned surfaces.

The quantitative effects of micropatterned laminin surfaces on neurite outgrowth and growth cone morphology were investigated. Using microlithography, 20- or 30-micron-wide laminin stripes were applied to the surface of a glass coverslip, alternating with BSA-coated glass stripes of the same dimension. Growth on these surfaces was strongly biased in the direction parallel to the stripes, but the mean length of outgrowth was reduced relative to that on uniform laminin surfaces. Growth cones were slightly more elongated on micropatterned surfaces than on controls and were aligned with the pattern. These results provide a starting point for examining the fundamental effects of micropatterned surfaces on neurite outgrowth and ways in which these may be useful in controlling and guiding neurite outgrowth for biotechnological applications.

Stochastic dynamics of the nerve growth cone and its microtubules during neurite outgrowth.

The controlled extension of neurites is essential not only for nervous system development, but also for effective nerve regeneration after injury. This process is critically dependent on microtubule assembly since axons fail to elongate in the presence of drugs which disrupt normal assembly dynamics. For this reason, neurite outgrowth is potentially controllable by manipulation of the assembly state of the intracellular array of microtubules. Therefore, understanding how microtubule assembly dynamics and neurite outgrowth are coupled, in the absence of drugs, can lend valuable insight into the control and guidance of the outgrowth process. In the present study we characterized the stochastic dynamics of neurite outgrowth and its corresponding microtubule array, which advances concomitantly with the advance of the nerve growth cone, the highly motile structure at the terminus of the growing neurite, using reported fluorescent microscopic image sequences (Tanaka and Kirschner, 1991, J. Cell Biol. 115:345-363). Although previously modeled as an uncorrelated random walk, the stochastic advance of the growth cone was found to be anticorrelated over a time scale of approximately 4 min, meaning that growth cone advances tended to be followed by growth cone retractions approximately 4 min later. The observed anticorrelation most likely reflects the periodic stops and starts of neurite outgrowth that have been reported anecdotally. A strikingly similar pattern of anticorrelation was also identified in the advance of the growth cone's microtubule array. Cross-correlation analysis showed that growth cone dynamics tended to precede microtubule dynamics on a time scale of approximately 0-2 min, while microtubules tended to precede growth cone dynamics on a approximately 0-20-s time scale, indicating a close temporal coupling between microtubule and growth cone dynamics. Finally, the scaling of the mean-squared displacements with time for both the growth cone and microtubules suggested a fractional Brownian motion model which accounts for the observed anticorrelation of growth cone and microtubule advance. (c) 1996 John Wiley & Sons, Inc.

A simple correlation for predicting effective diffusivities in immobilized cell systems.

A simple correlation method has been developed to predict effective diffusivities of small molecules in heterogeneous materials such as immobilized cell systems. This correlation uses a single diffusivity measurement at one cell volume fraction to predict diffusivities for any other volume fraction of cell. The method has been applied to 20 sets of published diffusivity measurements in immobilized cell systems and accurately predicts affective diffusivities of molecules for the full range of cell fractions. It may also be used to predict effective diffusivities in heterogeneous materials in which the diffusivity of a molecule in each phase and the volume fraction of each phase are known. (c) 1996 John Wiley & Sons, Inc.

Kinetics of microtubule catastrophe assessed by probabilistic analysis.

Microtubules are cytoskeletal filaments whose self-assembly occurs by abrupt switching between states of roughly constant growth and shrinkage, a process known as dynamic instability. Understanding the mechanism of dynamic instability offers potential for controlling microtubule-dependent cellular processes such as nerve growth and mitosis. The growth to shrinkage transitions (catastrophes) and the reverse transitions (rescues) that characterize microtubule dynamic instability have been assumed to be random events with first-order kinetics. By direct observation of individual microtubules in vitro and probabilistic analysis of their distribution of growth times, we found that while the slower growing and biologically inactive (minus) ends obeyed first-order catastrophe kinetics, the faster growing and biologically active (plus) ends did not. The non-first-order kinetics at plus ends imply that growing microtubule plus ends have an effective frequency of catastrophe that depends on how long the microtubules have been growing. This frequency is low initially but then rises asymptotically to a limiting value. Our results also suggest that an additional parameter, beyond the four parameters typically used to describe dynamic instability, is needed to account for the observed behavior and that changing this parameter can significantly affect the distribution of microtubule lengths at steady state.