Matrix Metalloproteinases and Glaucoma Treatment.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from in vivo and in vitro studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect

Calibration of Low-Frequency, Wide-Field Radio Interferometers Using Delay/Delay-Rate Filtering

We present a filtering technique that can be applied to individual baselines of wide-bandwidth, wide-field interferometric data to geometrically select regions on the celestial sphere that contain primary calibration sources. The technique relies on the Fourier transformation of wide-band frequency spectra from a given baseline to obtain one-dimensional "delay images", and then the transformation of a time-series of delay images to obtain two-dimensional "delay/delay-rate images." Source selection is possible in these images given appropriate combinations of baseline, bandwidth, integration time and source location. Strong and persistent radio frequency interference (RFI) limits the effectiveness of this source selection owing to the removal of data by RFI excision algorithms. A one-dimensional, complex CLEAN algorithm has been developed to compensate for RFI-excision effects. This approach allows CLEANed, source-isolated data to be used to isolate bandpass and primary beam gain functions. These techniques are applied to data from the Precision Array for Probing the Epoch of Reionization (PAPER) as a demonstration of their value in calibrating a new generation of low-frequency radio interferometers with wide relative bandwidths and large fields-of-view.Comment: 17 pages, 6 figures, 2009AJ....138..219

Latanoprost with high precision, piezo-print microdose delivery for IOP lowering: clinical results of the PG21 study of 0.4 µg daily microdose.

Background:Topical high-precision piezo-print delivery of microdoses of latanoprost achieved significant IOP reduction consistent with the eyedropper effect but with a 75% reduced exposure to drugs and preservatives. Prostaglandin analogs are a mainstay glaucoma therapy. However, conventional eyedroppers deliver 30-50 µL drops that greatly exceed the physiologic 7-µL ocular tear film capacity. Eyedropper overdosing floods the eye with excess drug compounds and preservatives, resulting in ocular surface toxicity, periorbitopathy, and other well-characterized ocular side effects. Piezoelectric high-precision microdosing provides targeted delivery that can reduce exposure to both drug and preservatives compared to conventional eyedropper delivery, with the potential to deliver similar biologic effect. Methods:Both eyes (N=60) of 30 healthy volunteers received single 8-µL microdoses of 0.005% latanoprost (0.4 µg; µRx-latanoprost) on the morning of Days 1 and 2 using a high-precision, piezo-print horizontal delivery system. Diurnal IOP was measured before and 2 days after microdosing. Main efficacy outcomes were diurnal IOP change after µRx-latanoprost microdosing and accurate microdosing success rates, and the primary safety outcome was adverse event (AE) incidence. Results:µRx-latanoprost reduced baseline IOP by 26% and 30% at 1 and 2 days postadministration, respectively. Successful topical dosing was achieved in 100% of technician-assisted deliveries. All patients successfully self-administered microdoses after receiving training. Microdose administration was well tolerated and did not result in any AEs. Conclusion:Microdosing of 0.4 µg of µRx-latanoprost achieved significant IOP reduction. Lower ocular exposure with topical prostaglandin analog microdosing can enable new therapeutic opportunities for optimizing glaucoma treatment. Microdosing may also be beneficial in reducing ocular side effects associated with excessive drug product and preservatives often used to treat chronic ocular diseases such as glaucoma

High-resolution wide-band Fast Fourier Transform spectrometers

We describe the performance of our latest generations of sensitive wide-band high-resolution digital Fast Fourier Transform Spectrometer (FFTS). Their design, optimized for a wide range of radio astronomical applications, is presented. Developed for operation with the GREAT far infrared heterodyne spectrometer on-board SOFIA, the eXtended bandwidth FFTS (XFFTS) offers a high instantaneous bandwidth of 2.5 GHz with 88.5 kHz spectral resolution and has been in routine operation during SOFIA's Basic Science since July 2011. We discuss the advanced field programmable gate array (FPGA) signal processing pipeline, with an optimized multi-tap polyphase filter bank algorithm that provides a nearly loss-less time-to-frequency data conversion with significantly reduced frequency scallop and fast sidelobe fall-off. Our digital spectrometers have been proven to be extremely reliable and robust, even under the harsh environmental conditions of an airborne observatory, with Allan-variance stability times of several 1000 seconds. An enhancement of the present 2.5 GHz XFFTS will duplicate the number of spectral channels (64k), offering spectroscopy with even better resolution during Cycle 1 observations.Comment: Accepted for publication in A&A (SOFIA/GREAT special issue

Asymmetric Patterns of Visual Field Defect in Primary Open-Angle and Primary Angle-Closure Glaucoma

Purpose: To compare the hemifield asymmetry of visual field (VF) loss in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) across all severity levels. Methods: A total of 522 eyes of 327 patients with POAG (mean age ± SD, 54.1 ± 12.4 years) and 375 eyes of 204 patients with PACG (67.3 ± 8.9 years) were included. Subjects meeting the definitions of POAG or PACG were included. Means of the total deviation (TD) values (Humphrey 24-2 VF) in the Glaucoma Hemifield Test (GHT) regions were calculated in early (≥ −6 dB), moderate (< −6 dB and ≥ −12 dB), and advanced (< −12 dB) stages of POAG and PACG eyes. Then the differences of the TD values between superior and inferior hemifield GHT regions of POAG and PACG eyes were calculated. Also, the relationship between the values of pattern SD (PSD) and mean TD (mTD) was compared between POAG and PACG. Results: In POAG eyes in the early stage, three regions (central, paracentral, and peripheral) in the superior hemifield had greater loss than their inferior counterparts; in moderate and advanced stages, all GHT regions in the superior hemifield had greater loss than their inferior counterparts. In PACG eyes, siginificantly fewer regions in the superior hemifield were significantly worse than their inferior counterpart, compared with POAG: one region (central) in early stage, two regions (central and peripheral) in moderate stage, and one region (central) in advanced stage. POAG eyes had greater PSD values than PACG eyes for given mean of TD values. Conclusions: In both POAG and PACG eyes, VF damage was more pronounced in superior hemifield than inferior hemifield; however, this tendency was more obvious in POAG eyes than in PACG eyes

Aqueous Angiography with Fluorescein and Indocyanine Green in Bovine Eyes.

PurposeWe characterize aqueous angiography as a real-time aqueous humor outflow imaging (AHO) modality in cow eyes with two tracers of different molecular characteristics.MethodsCow enucleated eyes (n = 31) were obtained and perfused with balanced salt solution via a Lewicky AC maintainer through a 1-mm side-port. Fluorescein (2.5%) or indocyanine green (ICG; 0.4%) were introduced intracamerally at 10 mm Hg individually or sequentially. With an angiographer, infrared and fluorescent images were acquired. Concurrent anterior segment optical coherence tomography (OCT) was performed, and fixable fluorescent dextrans were introduced into the eye for histologic analysis of angiographically positive and negative areas.ResultsAqueous angiography in cow eyes with fluorescein and ICG yielded high-quality images with segmental patterns. Over time, ICG maintained a better intraluminal presence. Angiographically positive, but not negative, areas demonstrated intrascleral lumens with anterior segment OCT. Aqueous angiography with fluorescent dextrans led to their trapping in AHO pathways. Sequential aqueous angiography with ICG followed by fluorescein in cow eyes demonstrated similar patterns.ConclusionsAqueous angiography in model cow eyes demonstrated segmental angiographic outflow patterns with either fluorescein or ICG as a tracer.Translational relevanceFurther characterization of segmental AHO with aqueous angiography may allow for intelligent placement of trabecular bypass minimally invasive glaucoma surgeries for improved surgical results

SOFIA observations of far-infrared hydroxyl emission toward classical ultracompact HII/OH maser regions

The hydroxyl radical (OH) is found in various environments within the interstellar medium (ISM) of the Milky Way and external galaxies, mostly either in diffuse interstellar clouds or in the warm, dense environments of newly formed low-mass and high-mass stars, i.e, in the dense shells of compact and ultracompact HII regions (UCHIIRs). Until today, most studies of interstellar OH involved the molecule's radio wavelength hyperfine structure (hfs) transitions. These lines are generally not in LTE and either masing or over-cooling complicates their interpretation. In the past, observations of transitions between different rotational levels of OH, which are at far-infrared wavelengths, have suffered from limited spectral and angular resolution. Since these lines have critical densities many orders of magnitude higher than the radio wavelength ground state hfs lines and are emitted from levels with more than 100 K above the ground state, when observed in emission, they probe very dense and warm material. We probe the warm and dense molecular material surrounding the UCHIIR/OH maser sources W3(OH), G10.62-0.39 and NGC 7538 IRS1 by studying the $^2\Pi_{{1/2}}, J = {3/2} - {1/2}$ rotational transition of OH in emission and, toward the last source also the molecule's $^2\Pi_{3/2}, J = 5/2 - 3/2$ ground-state transition in absorption. We used the Stratospheric Observatory for Infrared Astronomy (SOFIA) to observe these OH lines, which are near 1.84 THz ($163 \mu$m) and 2.51 THz ($119.3 \mu$m). We clearly detect the OH lines, some of which are blended with each other. Employing non-LTE radiative transfer calculations we predict line intensities using models of a low OH abundance envelope versus a compact, high-abundance source corresponding to the origin of the radio OH lines.Comment: Accepted for publication in A&A (SOFIA/GREAT special issue

A Scalable Correlator Architecture Based on Modular FPGA Hardware, Reuseable Gateware, and Data Packetization

A new generation of radio telescopes is achieving unprecedented levels of sensitivity and resolution, as well as increased agility and field-of-view, by employing high-performance digital signal processing hardware to phase and correlate large numbers of antennas. The computational demands of these imaging systems scale in proportion to BMN^2, where B is the signal bandwidth, M is the number of independent beams, and N is the number of antennas. The specifications of many new arrays lead to demands in excess of tens of PetaOps per second. To meet this challenge, we have developed a general purpose correlator architecture using standard 10-Gbit Ethernet switches to pass data between flexible hardware modules containing Field Programmable Gate Array (FPGA) chips. These chips are programmed using open-source signal processing libraries we have developed to be flexible, scalable, and chip-independent. This work reduces the time and cost of implementing a wide range of signal processing systems, with correlators foremost among them,and facilitates upgrading to new generations of processing technology. We present several correlator deployments, including a 16-antenna, 200-MHz bandwidth, 4-bit, full Stokes parameter application deployed on the Precision Array for Probing the Epoch of Reionization.Comment: Accepted to Publications of the Astronomy Society of the Pacific. 31 pages. v2: corrected typo, v3: corrected Fig. 1

LIME - a flexible, non-LTE line excitation and radiation transfer method for millimeter and far-infrared wavelengths

We present a new code for solving the molecular and atomic excitation and radiation transfer problem in a molecular gas and predicting emergent spectra. This code works in arbitrary three dimensional geometry using unstructured Delaunay latices for the transport of photons. Various physical models can be used as input, ranging from analytical descriptions over tabulated models to SPH simulations. To generate the Delaunay grid we sample the input model randomly, but weigh the sample probability with the molecular density and other parameters, and thereby we obtain an average grid point separation that scales with the local opacity. Our code does photon very efficiently so that the slow convergence of opaque models becomes traceable. When convergence between the level populations, the radiation field, and the point separation has been obtained, the grid is ray-traced to produced images that can readily be compared to observations. Because of the high dynamic range in scales that can be resolved using this type of grid, our code is particularly well suited for modeling of ALMA data. Our code can furthermore deal with overlapping lines of multiple molecular and atomic species.Comment: 13 pages, 12 figures, Accepted by A&A on 06/08/201