Simultaneous Intensity, Birefringence, and Flow Measurements with High-speed Fiber-based Optical Coherence Tomography

Optics Letters. Sep, 2002  |  Pubmed ID: 18026497

We demonstrate that tissue structure, birefringence, and blood flow can be imaged simultaneously by use of techniques of polarization-sensitive optical coherence tomography and phase-resolved optical Doppler tomography. An efficient data-acquisition procedure is implemented that optimizes the concurrent processing and display of all three image types. Images of in vivo human skin acquired with a high-speed fiber-based system are presented.

Invivo Depth-resolved Birefringence Measurements of the Human Retinal Nerve Fiber Layer by Polarization-sensitive Optical Coherence Tomography

Optics Letters. Sep, 2002  |  Pubmed ID: 18026517

To our knowledge, this is the first demonstration of in vivo depth-resolved birefringence measurements of the human retinal nerve fiber layer (RNFL) by use of polarization-sensitive optical coherence tomography (PS-OCT). Because glaucoma causes nerve fiber layer damage, which may cause loss of retinal birefringence, PS-OCT is a potentially useful technique for the early detection of glaucoma. We built a fiber-based PS-OCT setup that produces quasi-real-time images of the human retina in vivo . Preliminary measurements of a healthy volunteer showed that the double-pass phase retardation per unit depth of the RNFL near the optic nerve head is 39+/-6( degrees )/100microm .

Improved Signal-to-noise Ratio in Spectral-domain Compared with Time-domain Optical Coherence Tomography

Optics Letters. Nov, 2003  |  Pubmed ID: 14587817

A signal-to-noise ratio (SNR) analysis is presented for optical coherence tomography (OCT) signals in which time-domain performance is compared with that of the spectral domain. A significant SNR gain of several hundredfold is found for acquisition in the spectral domain. The SNR benefit is demonstrated experimentally in a hybrid time-domain-spectral-domain OCT system.

Real-time Multi-functional Optical Coherence Tomography

Optics Express. Apr, 2003  |  Pubmed ID: 19461791

We demonstrate real-time acquisition, processing, and display of tissue structure, birefringence, and blood flow in a multi-functional optical coherence tomography (MF-OCT) system. This is accomplished by efficient data processing of the phase-resolved inteference patterns without dedicated hardware or extensive modification to the high-speed fiber-based OCT system. The system acquires images of 2048 depth scans per second, covering an area of 5 mm in width x 1.2 mm in depth with real-time display updating images in a rolling manner 32 times each second. We present a video of the system display as images from the proximal nail fold of a human volunteer are taken.

In Vivo Dynamic Human Retinal Blood Flow Imaging Using Ultra-high-speed Spectral Domain Optical Coherence Tomography

Optics Express. Dec, 2003  |  Pubmed ID: 19471483

An ultra-high-speed spectral domain optical Doppler tomography (SD-ODT) system is used to acquire images of blood flow in a human retina in vivo, at 29,000 depth profiles (A-lines) per second and with data acquisition over 99% of the measurement time. The phase stability of the system is examined and image processing algorithms are presented that allow accurate determination of bi-directional Doppler shifts. Movies are presented of human retinal flow acquired at 29 frames per second with 1000 A-lines per frame over a time period of 3.28 seconds, showing accurate determination of vessel boundaries and time-dependent bi-directional flow dynamics in artery-vein pairs. The ultra-high-speed SD-ODT system allows visualization of the pulsatile nature of retinal blood flow, detects blood flow within the choroid and retinal capillaries, and provides information on the cardiac cycle. In summary, accurate video rate imaging of retinal blood flow dynamics is demonstrated at ocular exposure levels below 600 microW.

Ultrahigh-resolution High-speed Retinal Imaging Using Spectral-domain Optical Coherence Tomography

Optics Express. May, 2004  |  Pubmed ID: 19475080

We present the first ultrahigh-resolution optical coherence tomography (OCT) structural intensity images and movies of the human retina in vivo at 29.3 frames per second with 500 A-lines per frame. Data was acquired at a continuous rate of 29,300 spectra per second with a 98% duty cycle. Two consecutive spectra were coherently summed to improve sensitivity, resulting in an effective rate of 14,600 A-lines per second at an effective integration time of 68 micros. The turn-key source was a combination of two super luminescent diodes with a combined spectral width of more than 150 nm providing 4.5 mW of power. The spectrometer of the spectraldomain OCT (SD-OCT) setup was centered around 885 nm with a bandwidth of 145 nm. The effective bandwidth in the eye was limited to approximately 100 nm due to increased absorption of wavelengths above 920 nm in the vitreous. Comparing the performance of our ultrahighresolution SD-OCT system with a conventional high-resolution time domain OCT system, the A-line rate of the spectral-domain OCT system was 59 times higher at a 5.4 dB lower sensitivity. With use of a software based dispersion compensation scheme, coherence length broadening due to dispersion mismatch between sample and reference arms was minimized. The coherence length measured from a mirror in air was equal to 4.0 microm (n= 1). The coherence length determined from the specular reflection of the foveal umbo in vivo in a healthy human eye was equal to 3.5 microm (n = 1.38). With this new system, two layers at the location of the retinal pigmented epithelium seem to be present, as well as small features in the inner and outer plexiform layers, which are believed to be small blood vessels. ?2004 Optical Society of America.

In Vivo Birefringence and Thickness Measurements of the Human Retinal Nerve Fiber Layer Using Polarization-sensitive Optical Coherence Tomography

Journal of Biomedical Optics. Jan-Feb, 2004  |  Pubmed ID: 14715063

Glaucoma causes damage of the nerve fiber layer, which may cause loss of retinal birefringence. Therefore, PS-OCT is a potentially useful technique for the early detection of glaucoma. We built a fiber-based PS-OCT setup that produces real-time images of the human retina in vivo, coregistered with retinal video images of the location of PS-OCT scans. Preliminary measurements of a healthy volunteer show that the double-pass phase retardation per unit of depth of the RNFL is not constant and varies with location, with values between 0.18 and 0.37 deg/microm. A trend in the preliminary measurements shows that the nerve fiber layer located inferior and superior to the optic nerve head is more birefringent than the thinner layer of nerve fiber tissue in the temporal and nasal regions.

Birefringence Measurements in Human Skin Using Polarization-sensitive Optical Coherence Tomography

Journal of Biomedical Optics. Mar-Apr, 2004  |  Pubmed ID: 15065893

Optical coherence tomography enables cross-sectional imaging of tissue structure to depths of around 1.5 mm, at high-resolution and in real time. Incorporation of polarization sensitivity (PS) provides an additional contrast mechanism which is complementary to images mapping backscattered intensity only. We present here polarization-sensitive optical coherence tomography (OCT) images of human skin in vivo, demonstrating the ability of the technique to visualize and quantify the birefringent properties of skin. Variation in normal skin birefringence according to anatomical location is demonstrated, and discussed in relation to collagen distribution at each location. From measurements on a sample of five human volunteers, mean double-pass phase retardation rates of 0.340+/-0.143, 0.250+/-0.076, and 0.592+/-0.142 deg/microm were obtained for the dorsal hand, temple, and lower back regions, respectively. We demonstrate how averaging the Stokes parameters of backscattered light over a range of axial and lateral dimensions results in a reduction of speckle-induced noise. Examples of PS-OCT images from skin sites following wound healing and repair are also presented and discussed.

Polarization-sensitive Optical Coherence Tomography of Invasive Basal Cell Carcinoma

Journal of Biomedical Optics. Mar-Apr, 2004  |  Pubmed ID: 15065894

Skin cancer is the most common human malignancy, with basal cell carcinoma (BCC) the most frequent type. Aggressive forms of BCC are associated with extensive dermal invasion and destruction of collagen. Surgery is the most common treatment, but identification of tumor borders is a challenge. Polarization-sensitive optical coherence tomography (PS-OCT) is an optical method to examine collagen birefringence. To date, it has not been exploited for cancer management. As part of a pilot exploratory study to examine the use of OCT in skin cancer, we examined several tumors that pose a challenge to the surgeon due to their large size and histological subtype. In normal perilesional skin, OCT identifies epidermal and dermal structure; PS-OCT identified dermal birefringence. In BCC, tumors lost normal structure and gained the appearance of lobular impressions. PS-OCT identified an alteration of dermal birefringence. Examination of a border area revealed a gradual transition from more normal appearing image to frank tumor. These results indicate that PS-OCT can identify features that distinguish normal skin from tumor and may have the potential to guide surgeons in the treatment of aggressive skin cancer.

Thickness and Birefringence of Healthy Retinal Nerve Fiber Layer Tissue Measured with Polarization-sensitive Optical Coherence Tomography

Investigative Ophthalmology & Visual Science. Aug, 2004  |  Pubmed ID: 15277483

Thinning of the retinal nerve fiber layer and changes in retinal nerve fiber layer (RNFL) birefringence may both precede clinically detectable glaucomatous vision loss. Early detection of RNFL changes may enable treatment to prevent permanent loss of vision. Polarization-sensitive optical coherence tomography (PS-OCT) can provide objective information on RNFL thickness and birefringence.

Collagen Denaturation Can Be Quantified in Burned Human Skin Using Polarization-sensitive Optical Coherence Tomography

Burns : Journal of the International Society for Burn Injuries. Sep, 2004  |  Pubmed ID: 15302415

Quantifiable prognostic indicators are of considerable practical value following thermal injury. Collagen is a major component of the skin, and is known to undergo denaturation at the elevated temperatures associated with burns. The purpose of this study was to determine whether a recently developed, non-invasive imaging technique could detect and quantify collagen denaturation in burned human skin. Polarization-sensitive optical coherence tomography (PS-OCT) imaging was used to quantify collagen birefringence in normal human skin, and in skin excised from burn patients. Images were acquired and displayed in 1s, and demonstrated qualitative differences between normal and partial-thickness burned human skin. Birefringence loss due to thermal denaturation of collagen was quantified, with mean phase retardation rates for samples of 26 normal and 26 burned skin sites determined to be 0.401 +/- 0.020 and 0.249 +/- 0.017 degrees /microm, respectively (mean +/- S.E.M.), with this difference in sample means shown to be statistically significant (P < 0.000001). Analysis of the accuracy of the technique indicated that PS-OCT measurements may be made with resolution sufficient to distinguish between burns of varying severity. In conclusion, PS-OCT is capable of imaging and quantifying collagen denaturation in burned human skin, providing a new parameter against which post-injury outcome may be compared.

Advances in Optical Coherence Tomography Imaging for Dermatology

The Journal of Investigative Dermatology. Sep, 2004  |  Pubmed ID: 15304083

Optical coherence tomography (OCT) is a non-invasive imaging technique, which has previously demonstrated potential for use in dermatology. The purpose of this study is to demonstrate how improvements in image quality, speed, and functionality enable qualitative and quantitative information to be obtained from in vivo human skin. We developed a portable fiber-optic based OCT imaging device that requires only 1 second to simultaneously provide high-resolution images of skin structure, collagen birefringence, and blood flow. Images of normal human skin were acquired in vivo, and features compared with clinical and histologic observations. The layered structure and appendages of skin were apparent in conventional OCT images, and correlated well with corresponding histology. Polarization-sensitive OCT images simultaneously revealed birefringent regions within the dermis corresponding to the location of collagen fibers, as confirmed with polarized light microscopy. Properties of collagen-rich tissues including tendon and scar tissues were quantified. Location of blood flow was also displayed alongside structural and polarization-sensitive images. Significant improvements in OCT technology have been made since its early application in dermatology. In particular, combining the previously described structural and Doppler imaging functions with polarization-sensitive imaging increases the utility of the technique for rapid, non-invasive investigations in the skin.

Revision Anterior Cruciate Ligament Reconstruction with Nonirradiated Fresh-frozen Patellar Tendon Allograft

Arthroscopy : the Journal of Arthroscopic & Related Surgery : Official Publication of the Arthroscopy Association of North America and the International Arthroscopy Association. Oct, 2004  |  Pubmed ID: 15483538

To evaluate the effectiveness of a revision anterior cruciate ligament reconstruction with nonirradiated patellar tendon allograft used to salvage a failed index patellar tendon autograft procedure.

Jones Matrix Analysis for a Polarization-sensitive Optical Coherence Tomography System Using Fiber-optic Components

Optics Letters. Nov, 2004  |  Pubmed ID: 15584278

We present an analysis for polarization-sensitive optical coherence tomography that facilitates the unrestricted use of fiber and fiber-optic components throughout an interferometer and yields sample birefringence, diattenuation, and relative optic axis orientation. We use a novel Jones matrix approach that compares the polarization states of light reflected from the sample surface with those reflected from within a biological sample for pairs of depth scans. The incident polarization alternated between two states that are perpendicular in a Poincaré sphere representation to ensure proper detection of tissue birefringence regardless of optical fiber contributions. The method was validated by comparing the calculated diattenuation of a polarizing sheet, chicken tendon, and muscle with that obtained by independent measurement. The relative importance of diattenuation versus birefringence to angular displacement of Stokes vectors on a Poincaré sphere was quantified.

Comment on "Optical-fiber-based Mueller Optical Coherence Tomography"

Optics Letters. Dec, 2004  |  Pubmed ID: 15645809

We comment on the recent Letter by Jiao et al. [Opt. Lett. 28, 1206 (2003)] in which a polarization-sensitive optical coherence tomography system was presented. Interrogating a sample with two orthogonal incident polarization states cannot always recover birefringence correctly. A previously presented fiber-based polarization-sensitive system was inaccurately characterized, and its method of eliminating the polarization distortion caused by single-mode optical fiber was presented earlier by Saxer et al. [Opt. Lett. 25, 1355 (2000)].

Optic Axis Determination Accuracy for Fiber-based Polarization-sensitive Optical Coherence Tomography

Optics Letters. Oct, 2005  |  Pubmed ID: 16208908

We present a generalized analysis of fiber-based polarization-sensitive optical coherence tomography with an emphasis on determination of sample optic axis orientation. The polarization properties of a fiber-based system can cause an overall rotation in a Poincaré sphere representation such that the plane of possible measured sample optic axes for linear birefringence and diattenuation no longer lies in the QU-plane. The optic axis orientation can be recovered as an angle on this rotated plane, subject to an offset and overall indeterminacy in sign such that only the magnitude, but not the direction, of a change in orientation can be determined. We discuss the accuracy of optic axis determination due to a fundamental limit on the accuracy with which a polarization state can be determined as a function of signal-to-noise ratio.

Imaging the Mucosa of the Human Vocal Fold with Optical Coherence Tomography

The Annals of Otology, Rhinology, and Laryngology. Sep, 2005  |  Pubmed ID: 16240928

Discerning the layered microstructure of the vocal folds is critical for effective phonomicrosurgery. Optical coherence tomography (OCT), a noncontact, noninvasive technology that provides cross-sectional images by means of backscattered light, offers the potential for delineating these layers in vivo.

Spectral Domain Optical Coherence Tomography: Ultra-high Speed, Ultra-high Resolution Ophthalmic Imaging

Archives of Ophthalmology. Dec, 2005  |  Pubmed ID: 16344444

To introduce a new ophthalmic optical coherence tomography technology that allows unprecedented simultaneous ultra-high speed and ultra-high resolution.

Real-time Fiber-based Multi-functional Spectral-domain Optical Coherence Tomography at 1.3 Microm

Optics Express. May, 2005  |  Pubmed ID: 19495302

We demonstrate a high-speed multi-functional spectral-domain optical coherence tomography system, using a broadband light source centered at 1.3 microm and two InGaAs line scan cameras capable of acquiring individual axial scans in 24.4 micros, at a rate of 18,500 axial scans per second. Fundamental limitations on the accuracy of phase determination as functions of signal-to-noise ratio and lateral scan speed are presented and their relative contributions are compared. The consequences of phase accuracy are discussed for both Doppler and polarization-sensitive OCT measurements. A birefringence artifact and a calibration procedure to remove this artifact are explained. Images of a chicken breast tissue sample acquired with the system were compared to those taken with a time-domain OCT system for birefringence measurement verification. The ability of the system to image pulsatile flow in the dermis and to perform functional imaging of large volumes demonstrates the clinical potential of multifunctional spectral-domain OCT.

Effects of Sample Arm Motion in Endoscopic Polarization-sensitive Optical Coherence Tomography

Optics Express. Jul, 2005  |  Pubmed ID: 19498576

Motion of the sample arm fiber in optical coherence tomography (OCT) systems can dynamically alter the polarization state of light incident on tissue during imaging, with consequences for both conventional and polarization-sensitive (PS-)OCT. Endoscopic OCT is particularly susceptible to polarization-related effects, since in most cases, the transverse scanning mechanism involves motion of the sample arm optical fiber to create an image. We investigated the effects of a scanning sample arm fiber on the polarization state of light in an OCT system, and demonstrate that by referencing the state backscattered from within a sample to the measured state at the surface, changes in polarization state due to sample fiber motion can be isolated. The technique is demonstrated by high-speed PS-OCT imaging at 1 frame per second, with both linear and rotary scanning fiber-optic probes. Measurements were made on a calibrated wave plate, and endoscopic PS-OCT images of ex-vivo human tissues are also presented, allowing comparison with features in histologic sections.

Imaging the Human Vocal Folds in Vivo with Optical Coherence Tomography: a Preliminary Experience

The Annals of Otology, Rhinology, and Laryngology. Apr, 2006  |  Pubmed ID: 16676824

Optical coherence tomography (OCT) and polarization-sensitive OCT (PS-OCT) are promising noninvasive methods for in vivo, cross-sectional imaging of the microstructure of the vocal folds. Previous studies in other tissues have shown an axial resolution of less than 10 microm and a maximum imaging depth of about 2 mm. The objectives of this pilot study were to obtain images from the vocal folds of subjects who were being evaluated and/or treated for vocal fold disease and to evaluate how well normal and pathologic microstructure could be seen in these images.

Measurement of Collagen and Smooth Muscle Cell Content in Atherosclerotic Plaques Using Polarization-sensitive Optical Coherence Tomography

Journal of the American College of Cardiology. Apr, 2007  |  Pubmed ID: 17397678

The purpose of this study was to investigate the measurement of collagen and smooth muscle cell (SMC) content in atherosclerotic plaques using polarization-sensitive optical coherence tomography (PSOCT).

Fiber-optic Confocal Microscope Using a MEMS Scanner and Miniature Objective Lens

Optics Express. Jul, 2007  |  Pubmed ID: 19547251

We designed and constructed a single-fiber-optic confocal microscope (SFCM) with a microelectromechanical system (MEMS) scanner and a miniature objective lens. Axial and lateral resolution values for the system were experimentally measured to be 9.55 mum and 0.83 mum respectively, in good agreement with theoretical predictions. Reflectance images were acquired at a rate of 8 frames per second, over a 140 mum x 70 mum field-of-view. In anticipation of future applications in oral cancer detection, we imaged ex vivo and in vivo human oral tissue with the SFCM, demonstrating the ability of the system to resolve cellular detail.

Subcellular-resolution Molecular Imaging Within Living Tissue by Fiber Microendoscopy

Optics Express. Dec, 2007  |  Pubmed ID: 19550931

Conventional histopathology involves sampling, sectioning and staining of tissue specimens prior to microscopic evaluation, and provides diagnostic information at a single location and point in time. In vivo microscopy and molecular-targeted optical labeling are two rapidly developing fields, which together have the potential to provide anatomical and functional indications of disease by staining and imaging tissue in situ. To address the need for high-resolution imaging instrumentation, we have developed a compact, robust, and inexpensive fiber-optic microendoscopy system based around wide-field LED illumination, a flexible 1 mm diameter fiber-optic bundle, and a color CCD camera. We demonstrate the sub-cellular resolution imaging capabilities of the system through a series of experiments, beginning with simultaneous imaging of three different cancer cell lines in culture, each targeted with a distinct fluorescent label. We used the narrow diameter probe to access subcutaneous tumors in an in vivo murine model, allowing direct comparison of microendoscopy images with macroscopic images and histopathology. A surgically resected tissue specimen from the human oral cavity was imaged across the clinical margin, demonstrating qualitative and quantitative distinction between normal and cancerous tissue based on sub-cellular image features. Finally, the fiber-optic microendoscope was used on topically-stained normal human oral mucosa in vivo, resolving epithelial cell nuclei and membranes in real-time fluorescence images. Our results demonstrate that this imaging system can potentially complement conventional diagnostic techniques, and support efforts to translate emerging molecular-diagnostic and therapeutic agents into clinical use.

Phase 1 Study of a Combination AMA1 Blood Stage Malaria Vaccine in Malian Children

PloS One. 2008  |  Pubmed ID: 18270560

Apical Membrane Antigen-1 (AMA1) is one of the leading blood stage malaria vaccine candidates. AMA1-C1/Alhydrogel consists of an equal mixture of recombinant AMA1 from FVO and 3D7 clones of P. falciparum, adsorbed onto Alhydrogel. A Phase 1 study in semi-immune adults in Mali showed that the vaccine was safe and immunogenic, with higher antibody responses in those who received the 80 microg dose. The aim of this study was to assess the safety and immunogenicity of this vaccine in young children in a malaria endemic area.

Optical Contrast Agents and Imaging Systems for Detection and Diagnosis of Cancer

International Journal of Cancer. Journal International Du Cancer. Nov, 2008  |  Pubmed ID: 18712733

Molecular imaging has rapidly emerged as a discipline with the potential to impact fundamental biomedical research and clinical practice. Within this field, optical imaging offers several unique capabilities, based on the ability of cells and tissues to effect quantifiable changes in the properties of visible and near-infrared light. Beyond endogenous optical properties, the development of molecularly targeted contrast agents enables disease-specific morphologic and biochemical processes to be labeled with unique optical signatures. Optical imaging systems can then provide real-time visualization of pathophysiology at spatial scales from the subcellular to whole organ levels. In this article, we review fundamental techniques and recent developments in optical molecular imaging, emphasizing laboratory and clinical systems that aim to visualize the microscopic and macroscopic hallmarks of cancer.

Lead in Christmas Lights

Journal of Environmental Health. Dec, 2008  |  Pubmed ID: 19115717

A recent California proposition led to awareness that lead is a stabilizer in the Polyvinyl Chloride (PVC) jacketing that covers conductors in Christmas lights. The objective of this study is to examine the level of accessible lead in Christmas lights. Following U.S. Environmental Protection Agency (U.S. EPA) Lead Inspectors' procedures, researchers at Cornell University and in Nebraska conducted wipe samples and total lead content samples of newly purchased and older Christmas light sets. Samples were analyzed for lead content. Lead was present in varying amounts on all samples. The amount of lead from the Nebraska samples, normalized to length of strings, was independent of analyzing laboratory, analysis method, age of string, and repeat sampling, both immediately and after extended storage. A later analysis of these same strings by the Cornell team showed diminished quantities. Amounts of surface lead normalized to crude estimates of the area of light string indicated surface concentrations in excess of U.S. EPA clearance level for lead on window sills. Whether exposure to lead in Christmas lights affects blood lead levels in humans is unknown. No standards exist for lead content in this product, and no protocols exist for conducting tests on it. Therefore, consumers may wish to exercise caution to reduce possible exposure.

A Phase 1 Study of the Blood-stage Malaria Vaccine Candidate AMA1-C1/Alhydrogel with CPG 7909, Using Two Different Formulations and Dosing Intervals

Vaccine. Jun, 2009  |  Pubmed ID: 19410624

A Phase 1 study was conducted in 24 malaria naïve adults to assess the safety and immunogenicity of the recombinant protein vaccine apical membrane antigen 1-Combination 1 (AMA1-C1)/Alhydrogel with CPG 7909 in two different formulations (phosphate buffer and saline), and given at two different dosing schedules, 0 and 1 month or 0 and 2 months. Both formulations were well tolerated and frequency of local reactions and solicited adverse events was similar among the groups. Peak antibody levels in the groups receiving CPG 7909 in saline were not significantly different than those receiving CPG 7909 in phosphate. Peak antibody levels in the groups vaccinated at a 0,2 month interval were 2.52-fold higher than those vaccinated at a 0,1 month interval (p=0.037, 95% CI 1.03, 4.28). In vitro growth inhibition followed the antibody level: median inhibition was 51% (0,1 month interval) versus 85% (0,2 month interval) in antibody from samples taken 2 weeks post-second vaccination (p=0.056).

A Randomized Controlled Phase 2 Trial of the Blood Stage AMA1-C1/Alhydrogel Malaria Vaccine in Children in Mali

Vaccine. May, 2009  |  Pubmed ID: 19428923

A double blind, randomized, controlled Phase 2 clinical trial was conducted to assess the safety, immunogenicity, and biologic impact of the vaccine candidate Apical Membrane Antigen 1-Combination 1 (AMA1-C1), adjuvanted with Alhydrogel. Participants were healthy children 2-3 years old living in or near the village of Bancoumana, Mali. A total of 300 children received either the study vaccine or the comparator. No impact of vaccination was seen on the primary endpoint, the frequency of parasitemia measured as episodes >3000/microL/day at risk. There was a negative impact of vaccination on the hemoglobin level during clinical malaria, and mean incidence of hemoglobin <8.5 g/dL, in the direction of lower hemoglobin in the children who received AMA1-C1, although these differences were not significant after correction for multiple tests. These differences were not seen in the second year of transmission.

Zelrix: a Novel Transdermal Formulation of Sumatriptan

Headache. Jun, 2009  |  Pubmed ID: 19438727

This study evaluated the pharmacokinetic and tolerability profiles of Zelrix (NuPathe Inc., Conshohocken, PA, USA), the novel formulation of sumatriptan (formerly known as NP101).

Anti-apical-membrane-antigen-1 Antibody is More Effective Than Anti-42-kilodalton-merozoite-surface-protein-1 Antibody in Inhibiting Plasmodium Falciparum Growth, As Determined by the in Vitro Growth Inhibition Assay

Clinical and Vaccine Immunology : CVI. Jul, 2009  |  Pubmed ID: 19439523

Apical membrane antigen 1 (AMA1) and the 42-kDa merozoite surface protein 1 (MSP1(42)) are leading malaria vaccine candidates. Several preclinical and clinical trials have been conducted, and an in vitro parasite growth inhibition assay has been used to evaluate the biological activities of the resulting antibodies. In a U.S. phase 1 trial with AMA1-C1/Alhydrogel plus CPG 7909, the vaccination elicited anti-AMA1 immunoglobulin G (IgG) which showed up to 96% inhibition. However, antibodies induced by MSP1(42)-C1/Alhydrogel plus CPG 7909 vaccine showed less than 32% inhibition in vitro. To determine whether anti-MSP1(42) IgG had less growth-inhibitory activity than anti-AMA1 IgG in vitro, the amounts of IgG that produced 50% inhibition of parasite growth (Ab(50)) were compared for rabbit and human antibodies. The Ab(50)s of rabbit and human anti-MSP1(42) IgGs were significantly higher (0.21 and 0.62 mg/ml, respectively) than those of anti-AMA1 IgGs (0.07 and 0.10 mg/ml, respectively) against 3D7 parasites. Ab(50) data against FVO parasites also demonstrated significant differences. We further investigated the Ab(50)s of mouse and monkey anti-AMA1 IgGs and showed that there were significant differences between the species (mouse, 0.28 mg/ml, and monkey, 0.14 mg/ml, against 3D7 parasites). Although it is unknown whether growth-inhibitory activity in vitro reflects protective immunity in vivo, this study showed that the Ab(50) varies with both antigen and species. Our data provide a benchmark for antibody levels for future AMA1- or MSP1(42)-based vaccine development efforts in preclinical and clinical trials.

A Randomized and Controlled Phase 1 Study of the Safety and Immunogenicity of the AMA1-C1/Alhydrogel + CPG 7909 Vaccine for Plasmodium Falciparum Malaria in Semi-immune Malian Adults

Vaccine. Dec, 2009  |  Pubmed ID: 19874925

A double blind, randomized and controlled Phase 1 clinical trial was conducted to assess the safety and immunogenicity in malaria-exposed adults of the Plasmodium falciparum blood stage vaccine candidate Apical Membrane Antigen 1-Combination 1 (AMA1-C1)/Alhydrogel with and without the novel adjuvant CPG 7909. Participants were healthy adults 18-45 years old living in the village of Donéguébougou, Mali. A total of 24 participants received 2 doses one month apart of either 80 microg AMA1-C1/Alhydrogel or 80 microg AMA1-C1/Alhydrogel + 564 microg CPG 7909. The study started in October 2007 and completed follow up in May 2008. Both vaccines were well tolerated, with only mild local adverse events and no systemic adverse events judged related to vaccination. The difference in antibody responses were over 2-fold higher in the group receiving CPG 7909 for all time points after second vaccination and the differences are statistically significant (all p<0.05). This is the first use of the novel adjuvant CPG 7909 in a malaria-exposed population.

Phase 1 Safety and Immunogenicity Trial of the Plasmodium Falciparum Blood-stage Malaria Vaccine AMA1-C1/ISA 720 in Australian Adults

Vaccine. Mar, 2010  |  Pubmed ID: 20051276

A Phase 1 trial was conducted in malaria-naïve adults to evaluate the recombinant protein vaccine apical membrane antigen 1-Combination 1 (AMA1-C1) formulated in Montanide ISA 720 (SEPPIC, France), a water-in-oil adjuvant. Vaccinations were halted early due to a formulation issue unrelated to stability or potency. Twenty-four subjects (12 in each group) were enrolled and received 5 or 20 microg protein at 0 and 3 months and four subjects were enrolled and received one vaccination of 80 microg protein. After first vaccination, nearly all subjects experienced mild to moderate local reactions and six experienced delayed local reactions occurring at Day 9 or later. After the second vaccination, three subjects experienced transient grade 3 (severe) local reactions; the remainder experienced grade 1 or 2 local reactions. All related systemic reactogenicity was grade 1 or 2, except one instance of grade 3 malaise. Anti-AMA1-C1 antibody responses were dose dependent and seen following each vaccination, with mean antibody levels 2-3 fold higher in the 20 microg group compared to the 5 microg group at most time points. In vitro growth-inhibitory activity was a function of the anti-AMA1 antibody titer. AMA1-C1 formulated in ISA 720 is immunogenic in malaria-naïve Australian adults. It is reasonably tolerated, though some transient, severe, and late local reactions are seen.

Emerging Roles for Multimodal Optical Imaging in Early Cancer Detection: a Global Challenge

Technology in Cancer Research & Treatment. Apr, 2010  |  Pubmed ID: 20218743

Medical imaging technologies have become increasingly important in the clinical management of cancer, and now play key roles in cancer screening, diagnosis, staging, and monitoring response to treatment. Standard imaging modalities such as MRI, PET, and CT require significant financial resources and infrastructure, which limits access to these modalities to those patients in high-resource settings. In contrast, optical imaging strategies, with the potential for reduced cost and enhanced portability, are emerging as additional tools to facilitate the early detection and diagnosis of cancer. This article presents a vision for an expanding role for optical imaging in global cancer management, including screening, early detection at the point-of-care, biopsy guidance, and real-time histology. Multi-modal optical imaging - the combination of widefield and high resolution imaging - has the potential to aid in the detection and management of precancer and early cancer for traditionally underserved populations. Several recent widefield and high-resolution optical imaging technologies are described, along with requirements for implementing such devices into lower-resource - settings.

Transdermal Delivery of Sumatriptan for the Treatment of Acute Migraine

Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics. Apr, 2010  |  Pubmed ID: 20430314

SUMMARY: Migraine is a common, multisymptom disorder that can severely impact the daily activities of migraineurs. Triptans (primarily sumatriptan) are the most commonly prescribed treatment for migraine and are considered a relatively safe and effective initial therapy. Unfortunately, current sumatriptan formulations (i.e., oral, nasal, subcutaneous) may be associated with limitations that can result in patients' delaying or avoiding treatment. For oral formulations, these limitations include difficulty in taking an oral medication due to the nausea and vomiting that often accompany migraine, and inconsistent absorption, whereas nasal and subcutaneous formulations may be associated with low bioavailability and an undesirable rate of adverse events, respectively. An alternative to current formulations is transdermal drug delivery, particularly iontophoresis. Transdermal delivery has several advantages over current formulations, including avoidance of the gastrointestinal tract, controlled and sustained delivery, and convenient administration. This article reviews the in vitro, in vivo, and preclinical data supporting the use of iontophoresis for the delivery of sumatriptan, as well as the recent clinical data for Zelrix (NuPathe Inc., Conshohocken, PA), an iontophoretic sumatriptan patch currently in phase III development for the treatment of migraine.

A Fiber-optic Fluorescence Microscope Using a Consumer-grade Digital Camera for in Vivo Cellular Imaging

PloS One. 2010  |  Pubmed ID: 20585636

Early detection is an essential component of cancer management. Unfortunately, visual examination can often be unreliable, and many settings lack the financial capital and infrastructure to operate PET, CT, and MRI systems. Moreover, the infrastructure and expense associated with surgical biopsy and microscopy are a challenge to establishing cancer screening/early detection programs in low-resource settings. Improvements in performance and declining costs have led to the availability of optoelectronic components, which can be used to develop low-cost diagnostic imaging devices for use at the point-of-care. Here, we demonstrate a fiber-optic fluorescence microscope using a consumer-grade camera for in vivo cellular imaging.

Portable, Battery-operated, Low-cost, Bright Field and Fluorescence Microscope

PloS One. 2010  |  Pubmed ID: 20694194

This study describes the design and evaluation of a portable bright-field and fluorescence microscope that can be manufactured for $240 USD. The microscope uses a battery-operated LED-based flashlight as the light source and achieves a resolution of 0.8 microm at 1000x magnification in fluorescence mode. We tested the diagnostic capability of this new instrument to identify infections caused by the human pathogen, Mycobacterium tuberculosis. Sixty-four direct, decontaminated, and serially diluted smears were prepared from sputa obtained from 19 patients suspected to have M. tuberculosis infection. Slides were stained with auramine orange and evaluated as being positive or negative for M. tuberculosis with both the new portable fluorescence microscope and a laboratory grade fluorescence microscope. Concordant results were obtained in 98.4% of cases. This highly portable, low cost, fluorescence microscope may be a useful diagnostic tool to expand the availability of M. tuberculosis testing at the point-of-care in low resource settings.

Low-cost, Portable Optical Imaging Systems for Cancer Diagnosis

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2010  |  Pubmed ID: 21096559

Worldwide incidence and mortality rates due to cancer continue to rise, with the burden of disease increasingly shifting to developing countries. Several optical diagnostic methods such as diffuse optical tomography, wide-field autofluorescence imaging, confocal microscopy, and optical coherence tomography, are currently under development to enable earlier detection of cancer. However, these are primarily intended for use in healthcare facilities in industrialized countries. Using knowledge gained from early clinical studies with these large-scale systems, we have designed and tested low-cost, portable versions of these instruments. We propose that these systems may be used for early diagnosis and screening in developing countries, and that pilot clinical studies are warranted in these low-resource settings.

Low-cost Endomicroscopy in the Esophagus and Colon

The American Journal of Gastroenterology. Sep, 2011  |  Pubmed ID: 21897416

Toward a Low-cost Compact Array Microscopy Platform for Detection of Tuberculosis

Tuberculosis (Edinburgh, Scotland). Dec, 2011  |  Pubmed ID: 22079590

This paper describes the development of a microscope array capable of imaging separate fields of view without the need for opto-mechanical scanning components. This microscope array can be integrated with array illuminating optics, a full frame digital single lens reflex (DSLR) camera, and automated algorithms for the detection of Mycobacterium tuberculosis (MTB). The entire array will fit within the area of a typical sputum smear. A custom miniature objective has been designed for this microscope array that has a numerical aperture of 0.5, optical resolution of 0.63 μm, and a field of view that is 0.54 mm in diameter. A single prototype miniature objective of this design has been built, and images are presented demonstrating its imaging performance. Images are sufficiently high quality for diagnostic use. When fully integrated, this device has the potential to significantly improve performance compared to conventional microscopy systems and to enable more effective diagnosis of tuberculosis at the point of care.