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1.  Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine 
Smith, Kimberly Y. | Tierney, Camlin | Mollan, Katie | Venuto, Charles S. | Budhathoki, Chakra | Ma, Qing | Morse, Gene D. | Sax, Paul | Katzenstein, David | Godfrey, Catherine | Fischl, Margaret | Daar, Eric S. | Collier, Ann C. | Bolivar, Hector H. | Navarro, Sandra | Koletar, Susan L. | Gochnour, Diane | Seefried, Edward | Hoffman, Julie | Feinberg, Judith | Saemann, Michelle | Patterson, Kristine | Pittard, Donna | Currin, David | Upton, Kerry | Saag, Michael | Ray, Graham | Johnson, Steven | Santos, Bartolo | Funk, Connie A. | Morgan, Michael | Jackson, Brenda | Tebas, Pablo | Thomas, Aleshia | Kim, Ge-Youl | Klebert, Michael K. | Santana, Jorge L. | Marrero, Santiago | Norris, Jane | Valle, Sandra | Cox, Gary Matthew | Silberman, Martha | Shaik, Sadia | Lopez, Ruben | Vasquez, Margie | Daskalakis, Demetre | Megill, Christina | Shore, Jessica | Taiwo, Babafemi | Goldman, Mitchell | Boston, Molly | Lennox, Jeffrey | del Rio, Carlos | Lane, Timothy W. | Epperson, Kim | Luetkemeyer, Annie | Payne, Mary | Gripshover, Barbara | Antosh, Dawn | Reid, Jane | Adams, Mary | Storey, Sheryl S. | Dunaway, Shelia B. | Gallant, Joel | Wiggins, Ilene | Smith, Kimberly Y. | Swiatek, Joan A. | Timpone, Joseph | Kumar, Princy | Moe, Ardis | Palmer, Maria | Gothing, Jon | Delaney, Joanne | Whitely, Kim | Anderson, Ann Marie | Hammer, Scott M. | Yin, Michael T. | Jain, Mamta | Petersen, Tianna | Corales, Roberto | Hurley, Christine | Henry, Keith | Bordenave, Bette | Youmans, Amanda | Albrecht, Mary | Pollard, Richard B. | Olusanya, Abimbola | Skolnik, Paul R. | Adams, Betsy | Tashima, Karen T. | Patterson, Helen | Ukwu, Michelle | Rogers, Lauren | Balfour, Henry H. | Fox, Kathy A. | Swindells, Susan | Van Meter, Frances | Robbins, Gregory | Burgett-Yandow, Nicole | Davis, Charles E. | Boyce, Colleen | O'Brien, William A. | Casey, Gerianne | Morse, Gene D. | Hsaio, Chiu-Bin | Meier, Jeffrey L. | Stapleton, Jack T. | Mildvan, Donna | Revuelta, Manuel | Currin, David | El Sadr, Wafaa | Loquere, Avelino | El-Daher, Nyef | Johnson, Tina | Gross, Robert | Maffei, Kathyrn | Hughes, Valery | Sturge, Glenn | McMahon, Deborah | Rutecki, Barbara | Wulfsohn, Michael | Cheng, Andrew | Dix, Lynn | Liao, Qiming
This clinical trial identifies a significantly earlier time to virologic failure in women randomized to atazanavir/ritonavir compared to women randomized to efavirenz.
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.
Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII).
Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex.
Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential.
Clinical Trials Registration NCT00118898.
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
2.  In Vitro and In Vivo Imaging of Peptide-Encapsulated Polymer Nanoparticles for Cancer Biomarker Activated Drug Delivery 
Gelatin nanoparticles coated with Cathepsin D-specific peptides were developed as a vehicle for the targeted delivery of the cancer drug doxorubicin (DOX) to treat breast malignancy. Cathepsin D, a breast cancer cell secretion enzyme, triggered the release of DOX by digesting the protective peptide-coating layer of nanoparticles. Fabricated nanoparticles were successfully detected with ultrasound imaging in both in vitro conditions and in vivo mouse cancer models. Cell viability experiments were conducted to determine the efficacy of biomarker activation specific to breast cancer cell lines. These experimental results were compared with the outcome of a viability experiment conducted on noncancerous cells. Viability decreased in human MCF7 mammary adenocarcinoma and mouse 4T1 mammary carcinoma cells, while that of noncancerous 3T3 fibroblast cells remained unaffected. Next, a real-time video of nanoparticle flow in mouse models was obtained using in vivo ultrasound imaging. The fluorescent profile of DOX was used as a means to examine nanoparticle localization in vivo. Results show the distribution of nanoparticles concentrated primarily within bladder and tumor sites of subject mice bodies. These findings support the use of biomarker coated nanoparticles in target specific therapy for breast cancer treatment.
PMCID: PMC3962524  PMID: 23955780
Chemotherapy; doxorubicin; gelatin nanoparticles; in vivo ultrasound imaging; targeted drug delivery
3.  Assessing complexity of skin blood flow oscillations in response to locally applied heating and pressure in rats: implications for pressure ulcer risk 
Physica A  2013;392(20):10.1016/j.physa.2013.06.007.
The objective of this study was to investigate the effects of local heating on complexity of skin blood flow oscillations (BFO) under prolonged surface pressure in rats. Eleven Sprague–Dawley rats were studied: 7 rats underwent surface pressure with local heating (Δt = 10 °C) and 4 rats underwent pressure without heating. A pressure of 700 mmHg was applied to the right trochanter area of rats for 3 h. Skin blood flow was measured using laser Doppler flowmetry. The loading period was divided into nonoverlapping 30 min epochs. For each epoch, multifractal detrended fluctuation analysis (MDFA) was utilized to compute DFA coefficients and complexity of endothelia related metabolic, neurogenic, and myogenic frequencies of BFO. The results showed that under surface pressure, local heating led to a significant decrease in DFA coefficients of myogenic frequency during the initial epoch of loading period, a sustained decrease in complexity of myogenic frequency, and a significantly higher degree of complexity of metabolic frequency during the later phase of loading period. Surrogate tests showed that the reduction in complexity of myogenic frequency was associated with a loss of nonlinearity whereas increased complexity of metabolic frequency was associated with enhanced nonlinearity. Our results indicate that increased metabolic activity and decreased myogenic response due to local heating manifest themselves not only in magnitudes of metabolic and myogenic frequencies but also in their structural complexity. This study demonstrates the feasibility of using complexity analysis of BFO to monitor the ischemic status of weight-bearing skin and risk of pressure ulcers.
PMCID: PMC3849034  PMID: 24319315
complexity; loading pressure; local heating; pressure ulcers; skin blood flow
4.  Insights from gene arrays on the development and growth regulation of uterine leiomyomata 
Fertility and sterility  2002;78(1):114-121.
To use microarray analysis as an unbiased approach to identify genes involved in the induction and growth of uterine leiomyomata.
Screen by arrays for up to 12,000 genes in leiomyoma (L) and control myometrium (M) from nine patients.
University research laboratories.
Nine patients in the follicular and luteal phases of the menstrual cycle.
mRNA from L and M was converted to biotin-labeled cRNA and hybridized to cDNA oligonucleotide sequences on the arrays.
Main Outcome Measure(s)
Greater than two-fold change in gene expression between leiomyoma and matched myometrium.
Prominent among the 67 genes overexpressed in L relative to M were dlk or Pref-1, doublecortin, JM27, ionotropic glutamate receptor subunit 2, apolipoprotein E3, IGF2, semaphorin F, myelin proteolipid protein, MEST, frizzled, CRABP II, stromelysin-3, and TGFβ3. The genes dlk, IGF2, and MEST are paternally expressed imprinted genes, and the others are involved in tissue differentiation and growth. Prominent among the 78 genes down-regulated in L relative to M were alcohol dehydrogenases 1α–γ, tryptase, dermatopontin, thrombospondin, coxsackievirus receptor, nur77, and c-kit.
Arrays offer large-scale screening of mRNA expression, which will help us differentiate between the genes and metabolic pathways necessary for leiomyoma growth and those regulating myometrial contractions.
PMCID: PMC4143900  PMID: 12095500
c-kit; dlk; genomic imprinting; mast cells; myometrium; PPARγ; retinoic acid; RNA editing; RXRα; stem cell factor
5.  Techniques and Evaluation From a Cross-Platform Imaging Comparison of Quantitative Ultrasound Parameters in an In Vivo Rodent Fibroadenoma Model 
This contribution demonstrates that quantitative ultrasound (QUS) capabilities are platform independent, using an in vivo model. Frequency-dependent attenuation estimates, backscatter coefficient, and effective scatterer diameter estimates are shown to be comparable across four different ultrasound imaging systems with varied processing techniques. The backscatter coefficient (BSC) is a fundamental material property from which several QUS parameters are estimated; therefore, consistent BSC estimates among different systems must be demonstrated. This study is an intercomparison of BSC estimates acquired by three research groups (UIUC, UW, ISU) from four in vivo spontaneous rat mammary fibroadenomas using three clinical array systems and a single-element laboratory scanner system. Because of their highly variable backscatter properties, fibroadenomas provided an extreme test case for BSC analysis, and the comparison is across systems for each tumor, not across the highly heterogeneous tumors. RF echo data spanning the 1 to 12 MHz frequency range were acquired in three dimensions from all animals using each system. Each research group processed their RF data independently, and the resulting attenuation, BSC, and effective scatterer diameter (ESD) estimates were compared. The attenuation estimates across all systems showed the same trends and consistently fit the power-law dependence on frequency. BSCs varied among the multiple slices of data acquired by each transducer, with variations between transducers being of a similar magnitude as those from slice to slice. Variation between BSC estimates was assessed via functional signal-to-noise ratios derived from back-scatter data. These functional signal-to-noise ratios indicated that BSC versus frequency variations between systems ranged from negligible compared with the noise level to roughly twice the noise level. The corresponding functional analysis of variance (fANOVA) indicated statistically significant differences between BSC curves from different systems. However, root mean squared difference errors of the BSC values (in decibels) between different transducers and imaging platforms were less than half of the BSC magnitudes in most cases. Statistical comparison of the effective scatterer diameter (ESD) estimates resulted in no significant differences in estimates from three of the four transducers used for those estimates, demonstrating agreement among estimates based on the BSC. This technical advance demonstrates that these in vivo measurements can be made in a system-independent manner; the necessary step toward clinical implementation of the technology.
PMCID: PMC4090611  PMID: 25004506
6.  Properties of Membranes Derived from the Total Lipids Extracted from the Human Lens Cortex and Nucleus 
Biochimica et biophysica acta  2013;1828(6):1432-1440.
Human lens lipid membranes prepared using a rapid solvent exchange method from the total lipids extracted from the clear lens cortex and nucleus of 41- to 60-year-old donors were investigated using electron paramagnetic resonance spin-labeling. Profiles of the phospholipid alkyl-chain order, fluidity, oxygen transport parameter, and hydrophobicity were assessed across coexisting membrane domains. Membranes prepared from the lens cortex and nucleus were found to contain two distinct lipid environments, the bulk phospholipid-cholesterol domain and the cholesterol bilayer domain (CBD). The alkyl chains of phospholipids were strongly ordered at all depths, indicating that the amplitude of the wobbling motion of alkyl chains was small. However, profiles of the membrane fluidity, which explicitly contain time (expressed as the spin-lattice relaxation rate) and depend on the rotational motion of spin labels, show relatively high fluidity of alkyl chains close to the membrane center. Profiles of the oxygen transport parameter and hydrophobicity have a rectangular shape and also indicate a high fluidity and hydrophobicity of the membrane center. The amount of CBD was greater in nuclear membranes than in cortical membranes. The presence of the CBD in lens lipid membranes, which at 37°C showed a permeability coefficient for oxygen about 60% smaller than across a water layer of the same thickness, would be expected to raise the barrier for oxygen transport across the fiber cell membrane. Properties of human membranes are compared with those obtained for membranes made of lipids extracted from cortex and nucleus of porcine and bovine eye lenses.
PMCID: PMC3633468  PMID: 23438364
cholesterol; membrane domains; fluidity; hydrophobic barrier; oxygen permeation; EPR; spin labeling
7.  Influence of Microbubble Size on Postexcitation Collapse Thresholds for Single Ultrasound Contrast Agents Using Double Passive Cavitation Detection 
For the first time, and using an acoustical method, it has been shown experimentally that the inertial cavitation threshold pressure of an albumin-shelled microbubble is significantly correlated with its initial size.
PMCID: PMC3927843  PMID: 23661121
8.  Optimization of a Low Magnesium, Cholesterol-Containing Diet for the Development of Atherosclerosis in Rabbits 
Journal of food research  2013;2(1):168-178.
The cholesterol-fed rabbit is useful for atherosclerosis research. We describe development of a low-magnesium (Mg) cholesterol-containing diet to accelerate atherosclerosis in this model. Male New Zealand White rabbits were fed either chow or one of four atherogenic diets: 1% cholesterol 10% fat 0.11% Mg, 1% cholesterol 10% fat 0.40% Mg, 2% cholesterol 20% fat 0.11% Mg, or 2% cholesterol 20% fat 0.40% Mg. While feed intake decreased in cholesterol-fed rabbits, they were able to maintain their body weights. Rabbits consuming cholesterol experienced profound hypercholesterolemia and tissue lipid accumulation, with plasma cholesterol levels above 1500 mg/dl for all groups at the completion of the study. Liver and spleen lipid content and liver cholesterol content also increased. Aortic arch atheroma thickness was greatest in 1% cholesterol 10% fat 0.11% Mg animals. Tissue Mg levels decreased in cholesterol-fed animals compared to chow-fed controls, despite equal or greater serum Mg levels. Our results indicate that the 1% cholesterol 10% fat 0.11% Mg diet was optimal at promoting hypercholesterolemia and atherosclerosis while minimizing health complications for the animals. The low Mg cholesterol diet will be useful to other biomedical researchers interested in utilizing the rabbit for cardiovascular disease research.
PMCID: PMC3963699  PMID: 24672587
atherosclerosis; cardiovascular diseases; cholesterol; magnesium; rabbits
10.  Influences of Microbubble Diameter and Ultrasonic Parameters on In Vitro Sonothrombolysis Efficacy 
Quantify the effects of microbubble (MB) size, elasticity and pulsed ultrasonic parameters on in vitro sonothrombolysis (STBL: ultrasound-mediated thrombolysis) efficacy.
Monodispersive MBs with diameters of 1 μm or 3 μm were exposed to pulsed ultrasound (1 MHz or 3 MHz) to lyse rabbit blood clots. STBL efficacy (clot mass loss) was measured as functions of MB size and concentration, ultrasonic frequency and intensity, pulse duration (PD), pulse repeat frequency (PRF) and duty factor.
STBL at 1 MHz was more effective using 3 μm MBs and at 3 MHz using 1 μm MBs. STBL was generally more effective when 75% or more of MBs remained intact, especially for 3 μm MBs; and improving STBL by increasing PRF from 100 Hz to 400 Hz at 3 MHz was associated with increasing 3 μm MB survival. However, 60% of 1 μm MBs were destroyed during maximal STBL at 3 MHz, indicating that considerable MB collapse may be requisite for STBL under these conditions.
The ability to control MB size and elasticity permits utilizing a wide range of ultrasound parameters (frequency, intensity, etc.) to produce desired levels of STBL. Comparable, maximal STBL efficacy was achieved at twenty-fold lower intensity with 3 μm MBs (0.1 W/cm2) than with 1 μm MBs (2.0 W/cm2); a potential safety issue for in vivo STBL. Ultrasound parameters that maximized MB survival yielded maximal STBL efficacy; except with 1 μm MBs at 3 MHz where most MBs were destroyed.
PMCID: PMC3508303  PMID: 23106936
sonothrombolysis; microbubble; ultrasound; cavitation
11.  Transthoracic Cardiac Ultrasonic Stimulation Induces a Negative Chronotropic Effect 
The objective of this study is to investigate cardiac bioeffects resulting from ultrasonic stimulation using a specific set of acoustical parameters. Ten Sprague–Dawley rats were anesthetized and exposed to 1-MHz ultrasound pulses of 3-MPa peak rarefactional pressure and approximately 1% duty factor. The pulse repetition frequency started slightly above the heart rate and was decreased by 1 Hz every 10 s, for a total exposure duration of 30 s. The control group was composed of five rats. Two-way analysis of variance for repeated measures and Bonferroni post hoc tests were used to compare heart rate and ejection fraction, which was used as an index of myocardial contractility. It was demonstrated for the first time that transthoracic ultrasound has the potential to decrease the heart rate by ~20%. The negative chronotropic effect lasted for at least 15 min after ultrasound exposure and there was no apparent gross damage to the cardiac tissue.
PMCID: PMC3678613  PMID: 23221214
13.  Identification of Cellular Proteins Required for Replication of Human Immunodeficiency Virus Type 1 
AIDS Research and Human Retroviruses  2012;28(10):1329-1339.
Cellular proteins are essential for human immunodeficiency virus type 1 (HIV-1) replication and may serve as viable new targets for treating infection. Using gene trap insertional mutagenesis, a high-throughput approach based on random inactivation of cellular genes, candidate genes were found that limit virus replication when mutated. Disrupted genes (N=87) conferring resistance to lytic infection with several viruses were queried for an affect on HIV-1 replication by utilizing small interfering RNA (siRNA) screens in TZM-bl cells. Several genes regulating diverse pathways were found to be required for HIV-1 replication, including DHX8, DNAJA1, GTF2E1, GTF2E2, HAP1, KALRN, UBA3, UBE2E3, and VMP1. Candidate genes were independently tested in primary human macrophages, toxicity assays, and/or Tat-dependent β-galactosidase reporter assays. Bioinformatics analyses indicated that several host factors present in this study participate in canonical pathways and functional processes implicated in prior genome-wide studies. However, the genes presented in this study did not share identity with those found previously. Novel antiviral targets identified in this study should open new avenues for mechanistic investigation.
PMCID: PMC3448097  PMID: 22404213
14.  Method for Estimating Total Attenuation from a Spatial Map of Attenuation Slope for Quantitative Ultrasound Imaging 
Ultrasonic imaging  2013;35(2):162-172.
Estimating total ultrasound attenuation from backscatter data is essential in the field of quantitative ultrasound (QUS) because of the need to compensate for attenuation when estimating the backscatter coefficient and QUS parameters. This work uses a reference phantom method of attenuation estimation to create a spatial map of attenuation slope (AS) from backscatter radio-frequency (RF) data of three phantoms and a rat mammary adenocarcinoma tumor (MAT). The attenuation maps show changes in attenuation between different regions of the phantoms and the MAT tumor. Analyses of the attenuation maps of the phantoms suggest that the AS estimates are in good quantitative agreement with the known values for the phantoms. Furthermore, estimates of total attenuation from the attenuation maps are likewise in good quantitative agreement with known values.
PMCID: PMC3667609  PMID: 23493614
attenuation; attenuation slope; total attenuation; parametric image; quantitative ultrasound imaging; ultrasound
15.  AMP Deaminase 3 Deficiency Enhanced 5′-AMP Induction of Hypometabolism 
PLoS ONE  2013;8(9):e75418.
A hypometabolic state can be induced in mice by 5′-AMP administration. Previously we proposed that an underlying mechanism for this hypometabolism is linked to reduced erythrocyte oxygen transport function due to 5′-AMP uptake altering the cellular adenylate equilibrium. To test this hypothesis, we generated mice deficient in adenosine monophosphate deaminase 3 (AMPD3), the key catabolic enzyme for 5′-AMP in erythrocytes. Mice deficient in AMPD3 maintained AMPD activities in all tissues except erythrocytes. Developmentally and morphologically, the Ampd3−/− mice were indistinguishable from their wild type siblings. The levels of ATP, ADP but not 5′-AMP in erythrocytes of Ampd3−/− mice were significantly elevated. Fasting blood glucose levels of the Ampd3−/− mice were comparable to wild type siblings. In comparison to wild type mice, the Ampd3−/− mice displayed a deeper hypometabolism with a significantly delayed average arousal time in response to 5′-AMP administration. Together, these findings demonstrate a central role of AMPD3 in the regulation of 5′-AMP mediated hypometabolism and further implicate erythrocytes in this behavioral response.
PMCID: PMC3774621  PMID: 24066180
16.  Comparison of Ultrasound Attenuation and Backscatter Estimates in Layered Tissue-Mimicking Phantoms among Three Clinical Scanners 
Ultrasonic imaging  2012;34(4):209-221.
Backscatter and attenuation coefficient estimates are needed in many quantitative ultrasound strategies. In clinical applications, these parameters may not be easily obtained because of variations in scattering by tissues overlying a region of interest (ROI). The goal of this study is to assess the accuracy of backscatter and attenuation estimates for regions distal to nonuniform layers of tissue-mimicking materials. In addition, this work compares results of these estimates for “layered” phantoms scanned using different clinical ultrasound machines. Two tissue-mimicking phantoms were constructed, each exhibiting depth-dependent variations in attenuation or backscatter. The phantoms were scanned with three ultrasound imaging systems, acquiring radio frequency echo data for offline analysis. The attenuation coefficient and the backscatter coefficient (BSC) for sections of the phantoms were estimated using the reference phantom method. Properties of each layer were also measured with laboratory techniques on test samples manufactured during the construction of the phantom. Estimates of the attenuation coefficient versus frequency slope, α0, using backscatter data from the different systems agreed to within 0.24 dB/cm-MHz. Bias in the α0 estimates varied with the location of the ROI. BSC estimates for phantom sections whose locations ranged from 0 to 7 cm from the transducer agreed among the different systems and with theoretical predictions, with a mean bias error of 1.01 dB over the used bandwidths. This study demonstrates that attenuation and BSCs can be accurately estimated in layered inhomogeneous media using pulse-echo data from clinical imaging systems.
PMCID: PMC3667595  PMID: 23160474
attenuation; backscatter; ultrasound; inhomogeneity; quantitative ultrasound; tissue-mimicking phantom; interlaboratory; comparison
17.  Quantitative Ultrasonic Characterization of Diffuse Scatterers in the Presence of Structures That Produce Coherent Echoes 
Quantitative ultrasound (QUS) techniques that parameterize the backscattered power spectrum have demonstrated significant promise for ultrasonic tissue characterization. Some QUS parameters, such as the effective scatterer diameter (ESD), require the assumption that the examined medium contains uniform diffuse scatterers. Structures that invalidate this assumption can significantly affect the estimated QUS parameters and decrease performance when classifying disease. In this work, a method was developed to reduce the effects of echoes that invalidate the assumption of diffuse scattering. To accomplish this task, backscattered signal sections containing non-diffuse echoes were identified and removed from the QUS analysis. Parameters estimated from the generalized spectrum (GS) and the Rayleigh SNR parameter were compared for detecting data blocks with non-diffuse echoes. Simulations and experiments were used to evaluate the effectiveness of the method. Experiments consisted of estimating QUS parameters from spontaneous fibroadenomas in rats and from beef liver samples. Results indicated that the method was able to significantly reduce or eliminate the effects of non-diffuse echoes that might exist in the backscattered signal. For example, the average reduction in the relative standard deviation of ESD estimates from simulation, rat fibroadenomas, and beef liver samples were 13%, 30%, and 51%, respectively. The Rayleigh SNR parameter performed best at detecting non-diffuse echoes for the purpose of removing and reducing ESD bias and variance. The method provides a means to improve the diagnostic capabilities of QUS techniques by allowing separate analysis of diffuse and non-diffuse scatterers.
PMCID: PMC3428796  PMID: 22622974
18.  Properties of Fiber Cell Plasma Membranes Isolated from the Cortex and Nucleus of the Porcine Eye Lens 
Experimental Eye Research  2012;97(1):117-129.
The organization and physical properties of the lipid bilayer portion of intact cortical and nuclear fiber cell plasma membranes isolated from the eyes lenses of two-year-old pigs were studied using electron paramagnetic resonance (EPR) spin-labeling. Membrane fluidity, hydrophobicity, and the oxygen transport parameter (OTP) were assessed from the EPR spectra of precisely positioned spin labels. Intact cortical and nuclear membranes, which include membrane proteins, were found to contain three distinct lipid environments. These lipid environments were termed the bulk lipid domain, boundary lipid domain, and trapped lipid domain (lipids in protein aggregates). The amount of boundary and trapped lipids was greater in intact nuclear membranes than in cortical membranes. The properties of intact membranes were compared with the organization and properties of lens lipid membranes made of the total lipid extracts from the lens cortex or nucleus. In cortical lens lipid membranes, only one homogenous environment was detected, which was designated as a bulk lipid domain (phospholipid bilayer saturated with cholesterol). Lens lipid membranes prepared from the lens nucleus possessed two domains, assigned as a bulk lipid domain and a cholesterol bilayer domain (CBD). In intact nuclear membranes, it was difficult to discriminate the CBD, which was clearly detected in nuclear lens lipid membranes because the OTP measured in the CBD is the same as in the domain formed by trapped lipids. The two domains unique to intact membranes—namely, the domain formed by boundary lipids and the domain formed by trapped lipids—were most likely formed due to the presence of membrane proteins. It is concluded that formation of rigid and practically impermeable domains is enhanced in the lens nucleus, indicating changes in membrane composition that may help to maintain low oxygen concentration in this lens region.
PMCID: PMC3287047  PMID: 22326289
cholesterol; membrane domains; fluidity; hydrophobic barrier; oxygen permeation; EPR; spin labeling
Ultrasonics sonochemistry  2011;19(1):198-208.
Uniformly-sized preparations with average microbubble (MB) diameters from 1 µm to 7 µm were produced reliably by sonicating decafluorobutane-saturated solutions of serum albumin and dextrose. Detailed protocols for producing and size-separating the MBs are presented, along with the effects that changing each production parameter (serum albumin concentration, sonication power, sonication time, etc.) had on MB size distribution and acoustic stability. These protocols can be used to produce MBs for experimental applications or serve as templates for developing new protocols that yield MBs with physical and acoustic properties better suited to specific applications. Size stability and ultrasonic performance quality control tests were developed to assure that successive MB preparations perform identically and to distinguish the physical and acoustic properties of identically sized MBs produced with different serum albumin-dextrose formulations and sonication parameters. MBs can be stored at 5°C for protracted periods (2 weeks to one year depending on formulation).
PMCID: PMC3152625  PMID: 21689961
microbubble; ultrasound; contrast agent; production; sonication; cavitation
Nature Medicine  2011;17(12):1619-1626.
Nitric Oxide (NO) plays a critical role in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (Asl) deficiency exhibits a distinct phenotype manifest by multi-organ dysfunction and NO deficiency. Loss of Asl leads to reduced NO synthesis due to decreased endogenous arginine synthesis as well as reduced utilization of extracellular arginine for NO production in both humans and mice. Hence, ASL as seen in other species through evolution has a structural function in addition to its catalytic activity. Importantly, therapy with nitrite rescued the tissue autonomous NO deficiency in hypomorphic Asl mice, while a NOS independent NO donor restored NO-dependent vascular reactivity in subjects with ASL deficiency. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as treatment of NO-related diseases.
PMCID: PMC3348956  PMID: 22081021
21.  Contrast Ultrasound Imaging of the Aorta Alters Vascular Morphology and Circulating von Willebrand Factor in Hypercholesterolemic Rabbits 
Ultrasound contrast agents (UCAs) are intravenously infused microbubbles that add definition to ultrasonic images. Ultrasound contrast agents continue to show clinical promise in cardiovascular imaging, but their biological effects are not known with confidence. We used a cholesterol-fed rabbit model to evaluate these effects when used in conjunction with ultrasound (US) to image the descending aorta.
Male New Zealand White rabbits (n = 41) were weaned onto an atherogenic diet containing 1% cholesterol, 10% fat, and 0.11% magnesium. At 21 days, rabbits were exposed to contrast US at 1 of 4 pressure levels using either the UCA Definity (Lantheus Medical Imaging, Inc, North Billerica, MA) or a saline control (n = 5 per group). Blood samples were collected and analyzed for lipids and von Willebrand factor (vWF), a marker of endothelial function. Animals were euthanized at 42 days, and tissues were collected for histologic analysis.
After adjustment for pre-exposure vWF, high-level US (in situ [at the aorta] peak rarefactional pressure of 1.4 or 2.1 MPa) resulted in significantly lower vWF 1 hour post exposure (P = .0127; Padj < .0762). This difference disappeared within 24 hours. Atheroma thickness in the descending aorta was lower in animals receiving the UCA compared to animals receiving saline.
Contrast US affected the descending aorta, as evidenced by two separate outcome measures. These results may be a first step in elucidating a previously unknown biological effect of UCAs. Further research is warranted to characterize the effects of this procedure.
PMCID: PMC3428799  PMID: 22535718
analysis of covariance; atherosclerosis; biomarkers; contrast media; endothelium; microbubbles; ultrasound
22.  Biocompatibility of Pooled Human Immunoglobulin (Gamunex 10%™) with Ocular Infusion Solutions (BSS™ and BSS Plus™): An In Vitro Evaluation of a Potential Antitoxin Treatment for Infectious Endophthalmitis 
Gamunex 10% (Talecris Biotherapeutics, Research Triangle Park, NC), a commercially available preparation of pooled human immunoglobulin G, has been proposed as an antitoxin therapy against bacterial toxins released in infectious endophthalmitis. Its biocompatibility with two commonly used intraocular infusion fluids was evaluated to determine feasibility of its clinical application in endophthalmitis treatment.
Gamunex 10% was mixed with BSS or BSS Plus (Alcon Laboratories, Fort Worth, TX) such that it constituted a range of 1.25%–50% by volume. Osmolality, pH, optical density, and ionic strength were measured across this range of concentrations.
The amount of pH reduction with increasing concentrations of Gamunex 10% was similar for both BSS and BSS Plus. In BSS Plus, solutions containing up to 20% by volume of Gamunex 10% remained at near-physiologic pH (∼7.0 or above). No physiologically significant changes in osmolality or optical density measurements that would be anticipated to have profound physiological effects were observed at any of the measured concentrations, nor was there visual evidence of tubidity/precipitation. A gradual increase in ionic strength was observed with increasing concentrations of Gamunex 10%.
Potentially therapeutic mixtures of Gamunex 10% in 2 commonly used intraocular infusion fluids, BSS and BSS Plus, showed no evidence of bioincompatibility when the solutions were evaluated for changes in osmolality, pH, ionic strength, aggregation, or precipitation.
PMCID: PMC3146742  PMID: 21631364
23.  Ultrasound Contrast Agents Affect the Angiogenic Response 
Journal of Ultrasound in Medicine  2011;30(7):933-941.
The interaction of ultrasound contrast agents (UCAs) and ultrasound (US) provides a way to spatially and temporally target tissues. Recently, UCAs have been used therapeutically to induce localized angiogenesis. Ultrasound contrast agents, however, have been documented to induce negative bioeffects. To further understand the balance of risks and benefits of UCAs and to examine the mechanism of US-UCA–induced angiogenesis, this study explored the role of UCAs, in particular Definity (Lantheus Medical Imaging, Inc, North Billerica, MA), in producing an angiogenic response.
The gracilis muscles of Sprague Dawley rats were exposed to 1-MHz US. The rats were euthanized the same day or allowed to recover for 3 or 6 days post exposure (DPE). Ultrasound peak rarefactional pressures (Prs) of 0.25, 0.83, 1.4, and 2.0 MPa were used while rats were infused with either saline or Definity. Assessments for angiogenesis included capillary density, inflammation, and vascular endothelial growth factor (VEGF), both acutely (0 DPE) and at 3 and 6 DPE.
The results of this study suggest that the angiogenic response is dependent on infusion media, Pr, and DPE. While capillary density did not reach significance, VEGF expression was significant for infusion media, Pr, and DPE with inflammation co-occurrence (P < .05).
These results suggest that the angiogenic response is elicited by a mechanical effect of US-UCA stimulation of VEGF that is potentially optimized when collapse occurs.
PMCID: PMC3401069  PMID: 21705726
angiogenesis; proangiogenic therapy; therapeutic ultrasound; ultrasound contrast agent; ultrasound-induced bioeffects; vascular endothelial growth factor
24.  Ultrasonic Attenuation and Backscatter Coefficient Estimates of Rodent-Tumor-Mimicking Structures: Comparison of Results among Clinical Scanners 
Ultrasonic Imaging  2011;33(4):233-250.
In vivo estimations of the frequency-dependent acoustic attenuation (α) and backscatter (η) coefficients using radio frequency (RF) echoes acquired with clinical ultrasound systems must be independent of the data acquisition setup and the estimation procedures. In a recent in vivo assessment of these parameters in rodent mammary tumors, overall agreement was observed among α and η estimates using data from four clinical imaging systems. In some cases, particularly in highly attenuating heterogeneous tumors, multi-system variability was observed. This paper compares α and η estimates of a well-characterized rodent-tumor-mimicking homogeneous phantom scanned using 7 transducers with the same four clinical imaging systems: a Siemens Acuson S2000, an Ultrasonix RP, a Zonare, and a VisualSonics Vevo2100. α and η estimates of lesion-mimicking spheres in the phantom were independently assessed by three research groups, who analyzed their system’s RF echo signals. Imaging-system-based estimates of α and η of both lesion-mimicking spheres were comparable to through-transmission laboratory estimates and to predictions using Faran’s theory, respectively. A few notable variations in results among the clinical systems were observed, but the average and maximum percent difference between α estimates and laboratory-assessed values was 11% and 29%, respectively. Excluding a single outlier dataset, the average and maximum average difference between η estimates for the clinical systems and values predicted from scattering theory was 16% and 33%, respectively. These results were an improvement over previous inter-laboratory comparisons of attenuation and backscatter estimates. Although the standardization of our estimation methodologies can be further improved, this study validates our results from previous rodent breast-tumor model studies.
PMCID: PMC3384732  PMID: 22518954
Attenuation coefficient; backscatter coefficient; phantom; quantitative ultrasound
25.  Analysis of Human Fibroadenomas Using Three-Dimensional Impedance Maps 
IEEE transactions on medical imaging  2011;30(6):1206-1213.
Three-dimensional impedance maps (3DZMs) are virtual volumes of acoustic impedance values constructed from histology to represent tissue microstructure acoustically. From the 3DZM, the ultrasonic backscattered power spectrum can be predicted and model based scatterer properties, such as effective scatterer diameter (ESD), can be estimated. Additionally, the 3DZM can be exploited to visualize and identify possible scattering sites, which may aid in the development of more effective scattering models to better represent the ultrasonic interaction with underlying tissue microstructure. In this study, 3DZMs were created from a set of human fibroadenoma samples. ESD estimates were made assuming a fluid-filled sphere form factor model from 3DZMs of volume 300 × 300 × 300 µm. For a collection of 33 independent human fibroadenoma tissue samples, the ESD was estimated to be 111 ± 40.7 µm. The 3DZMs were then investigated visually to identify possible scattering sources which conformed to the estimated model scatterer dimensions. This estimation technique allowed a better understanding of the spatial distribution and variability of the estimates throughout the volume.
PMCID: PMC3277289  PMID: 21278015
Biomedical ultrasound; tissue modeling; ultra-sonic backscatter analysis; ultrasound simulation

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