Anabolic implants alter abundance of mRNA involved in muscle growth, metabolism, and inflammation in the longissimus of Angus steers in the feedlot.

The majority of beef cattle in the United States often receive at least one anabolic implant resulting in improved growth, feed efficiency, and environmental and economic sustainability. However, the physiological and molecular mechanisms through which anabolic implants increase skeletal muscle growth of beef cattle remain elusive. The objective of this study was to identify transcriptional changes occurring in skeletal muscle of steers receiving anabolic implants containing different steroid hormones. Forty-eight steers were stratified by weight into 1 of 4 (n = 12/treatment) implant treatment groups: (1) estradiol (ImpE2; 25.7 mg E2; Compudose, Elanco Animal Health, Greenfield, IN), (2) trenbolone acetate (ImpTBA; 200 mg TBA; Finaplix-H, Merck Animal Health, Madison, NJ), (3) combination (ImpETBA; 120 mg TBA + 24 mg E2; Revalor-S, Merck Animal Health), or (4) no implant (CON). Skeletal muscle biopsies were taken from the longissimus 2 and 10 d post-implantation. The mRNA abundance of 94 genes associated with skeletal muscle growth was examined. At 10 d post-implantation, steers receiving ImpETBA had greater (P = 0.02) myoblast differentiation factor 1 transcript abundance than CON. Citrate synthase abundance was increased (P = 0.04) in ImpETBA steers compared to CON steers. In ImpE2 steers 10 d post-implantation, muscle RING finger protein 1 decreased (P = 0.05) compared to CON steers, and forkhead box protein O4 decreased (P = 0.05) in ImpETBA steers compared to CON steers. Interleukin-6 abundance tended to be increased (P = 0.09) in ImpE2 steers compared to both ImpETBA and CON steers. Furthermore, interleukin-10 mRNA abundance tended to be increased (P = 0.06) in ImpTBA steers compared to ImpETBA steers. Leptin receptor abundance was reduced (P = 0.01) in both ImpE2 and ImpTBA steers when compared to CON steers. Abundance of phosphodiesterase 4B was increased (P = 0.04) in ImpTBA steers compared to CON steers 2 d post-implantation. Taken together, the results of this research demonstrate that estradiol increases skeletal muscle growth via pathways related to nutrient partitioning and mitochondria function, while trenbolone acetate improves steer skeletal muscle growth via pathways related to muscle growth.

Associations of Arthritis-Attributable Interference with Routine Life Activities: A Modifiable Source of Compromised Quality-of-Life.

OBJECTIVE: Arthritis patients experience the impact of disease beyond routinely assessed clinical measures. We characterized arthritis-attributable interference in four important routine life domains: 1) recreation/leisure/hobbies; 2) household chores; 3) errands/shopping; and 4) social activities. METHODS: Participants were from the Arthritis Conditions Health Effects Survey (2005-2006), a cross-sectional survey of noninstitutionalized US adults 45 years or older with doctor-diagnosed arthritis (n = 1793). We estimated the prevalence of "a lot" of arthritis-attributable interference and quantified the associations between sociodemographic, clinical, and psychological characteristics and "a lot" of arthritis-attributable interference (vs "a little" or "none") in each domain using prevalence ratios (PRs) in multivariable (MV)-adjusted logistic regression models. RESULTS: An estimated 1 in 5 to 1 in 4 adults with arthritis reported "a lot" of arthritis-attributable interference in recreation/leisure/hobbies (27%), household chores (25%), errands/shopping (22%), and social activities (18%). The highest prevalence of "a lot" of arthritis-attributable interference was for those unable to work/disabled or reporting severe arthritis symptoms (pain, stiffness, fatigue), anxiety, depression, or no/low confidence in ability to manage arthritis, across domains. In MV-adjusted models, those unable to work/disabled, currently seeing a doctor, or reporting fair/poor self-rated health, severe joint pain, anxiety, or no/low confidence in ability to manage arthritis were more likely to report arthritis-attributable interference than their respective counterparts. Magnitudes varied by domain but were consistently strongest for those unable to work/disabled (MV PR range = 1.8-2.5) and with fair/poor health (MV PR range = 1.7-2.7). CONCLUSION: Many characteristics associated with arthritis-attributable interference in routine life activities are potentially modifiable, suggesting unmet need for use of existing evidence-based interventions that address these characteristics and reduce interferences to improve quality of life.

Temporal resolution of dynamic angiography using flat panel volume CT: in vivo evaluation of time-dependent vascular pathologies.

BACKGROUND AND PURPOSE: Recently introduced fpVCT scanners can capture volumetric (4D) time-varying projections enabling whole-organ dynamic CTA imaging. The main objective of this study was to assess the temporal resolution of dynamic CTA in discriminating various phases of rapid and slow time-dependent neurovascular pathologies in animal models. MATERIALS AND METHODS: Animal models were created to assess phasic blood flow, subclavian steal phenomena, saccular aneurysms, and neuroperfusion under protocols approved by the SRAC. Animals with progressively increasing heart rate-Macaca sylvanus (~100 bpm), Oryctolagus cuniculus (NZW rabbit) (~150 bpm), Rattus norvegicus (~300 bpm), Mus musculus (~500 bpm)-were imaged to challenge the temporal resolution of the system. FpVCT, a research prototype with a 25 × 25 × 18 cm coverage, was used for dynamic imaging with the gantry rotation time varying from 3 to 5 seconds. Volumetric datasets with 50% temporal overlap were reconstructed; 4D datasets were analyzed by using the Leonardo workstation. RESULTS: Dynamic imaging by using fpVCT was capable of demonstrating the following phenomena: 1) subclavian steal in rabbits (ΔT ≅ 3-4 seconds); 2) arterial, parenchymal, and venous phases of blood flow in mice (ΔT ≅ 2 seconds), rabbits (ΔT ≅ 3-4 seconds), and Macaca sylvanus (ΔT ≅ 3-4 seconds); 3) sequential enhancement of the right and left side of the heart in Macaca sylvanus and white rabbits (ΔT ≅ 2 seconds); and 4) different times of the peak opacification of cervical and intracranial arteries, venous sinuses, and the jugular veins in these animals (smallest, ΔT ≅ 1.5-2 seconds). The perfusion imaging in all animals tested was limited due to the fast transit time through the brain and the low contrast resolution of fpVCT. CONCLUSIONS: Dynamic imaging by using fpVCT can distinguish temporal processes separated by >1.5 seconds. Neurovascular pathologies with a time constant >1.5 seconds can be evaluated noninvasively by using fpVCT.

Cardiac susceptibility artifacts arising from the heart-lung interface.

Cardiac MRI studies often show susceptibility artifacts along the inferoapical myocardial margin in both human and in vivo animal experiments at field strengths of 1.5T and greater. This study was designed to determine the cause of these artifacts in porcine myocardium at 3T. Gradient echo images were obtained under various anatomic and physiologic conditions to systematically study potential sources of local susceptibility gradients. Lung resection in the open-chested, euthanized swine was the only intervention that eliminated the artifact. The data suggest that in the porcine model, the heart-lung interface is the primary cause of these artifacts. Magn Reson Med 45:341-345, 2001.

Porcine coronary imaging in vivo by optical coherence tomography.

OBJECTIVE: A high-resolution coronary artery imaging modality has the potential to address important diagnostic and management problems in cardiology. Optical coherence tomography (OCT) is a promising new optical imaging technique with a resolution of approximately 10 microm. The purpose of this study was to use a new OCT catheter to demonstrate the feasibility of performing OCT imaging of normal coronary arteries, intimal dissections, and deployed stents in vivo. METHODS AND RESULTS: Normal coronary arteries, intimal dissections, and stents were imaged in five swine with OCT and compared with intravascular ultrasound (IVUS). In the normal coronary arteries, visualization of all of the layers of the vessel wall was achieved with a saline flush, including the intima which was not identified by IVUS. Following dissection, detailed layered structures including intimal flaps, intimal defects, and disruption of the medial wall were visualized by OCT. IVUS failed to show clear evidence of intimal and medial disruption. Finally, the microanatomic relationships between stents and the vessel walls were clearly identified only by OCT. CONCLUSIONS: In this preliminary experiment, we have demonstrated that in vivo OCT imaging of normal coronary arteries, intimal dissections, and deployed stents is feasible, and allows identification of clinically relevant coronary artery morphology with high-resolution and contrast.

Myocardial fiber shortening in humans: initial results of MR imaging.

PURPOSE: To use diffusion-sensitive magnetic resonance (MR) imaging to obtain images of fiber orientation in vivo and to map fiber shortening in humans by means of integrating such data with strain images. MATERIALS AND METHODS: Images of fiber shortening for midventricular short-axis sections were acquired in eight healthy subjects. Fiber orientation maps obtained by means of diffusion-sensitive MR imaging were coregistered with systolic strain maps obtained by means of velocity-sensitive MR imaging. Fiber shortening was quantified by use of the component of systolic strain in the fiber direction. RESULTS: The results were reproducible among subjects and were consistent with published values. MR imaging of myocardial fibers showed axisymmetric progression of fiber angles from -90 degrees epicardially to +90 degrees endocardially, with maxima near 0 degrees. Fiber shortening (mean, 0.12 +/- 0.01 [SD]) was more uniform than radial, circumferential, longitudinal, or cross-fiber strain or any principal strain. Fiber orientation coincided with the direction of maximum contraction epicardially, with that of minimum contraction endocardially, and varied between these extremes linearly with wall depth (r = 0.6). CONCLUSION: Registered diffusion and strain MR imaging can be used quantitatively to map fiber orientation and its relations to myocardial deformation in humans.

Noninvasive imaging for the diagnosis of coronary artery disease: focusing the development of new diagnostic technology.

BACKGROUND: New tests, such as magnetic resonance imaging (MRI) and electron-beam computed tomography (CT), are being developed for the diagnosis of coronary artery disease. OBJECTIVE: To determine the conditions that a new test must meet to be a cost-effective alternative to established imaging tests. DESIGN: Decision model and cost-effectiveness analysis. DATA SOURCES: Literature review and meta-analysis. TARGET POPULATION: 55-year-old men and 65-year-old women presenting with chest pain. TIME HORIZON: Lifetime of the patient. PERSPECTIVE: Health care policy. INTERVENTIONS: MRI, electron-beam CT, exercise echocardiography, exercise single-photon emission CT, and coronary angiography. OUTCOME MEASURES: Target sensitivity and specificity values for a new noninvasive test. RESULTS OF BASE-CASE ANALYSIS: Assuming that society is willing to pay $75000 per quality-adjusted life-year (QALY) gained, a new test that costs $1000 would need a sensitivity of 94% and a specificity of 90% to be cost-effective. RESULTS OF SENSITIVITY ANALYSIS: Assuming that society is willing to pay $50000 per QALY gained, a new test that costs $1000 or more would never be cost-effective. For a test that costs $500, the sensitivity and specificity must each be 95%. CONCLUSIONS: New imaging techniques, such as MRI and electron-beam CT, must be relatively inexpensive and have excellent sensitivity and specificity to be cost-effective compared with other techniques for the diagnosis of coronary artery disease. Similar analyses in other areas of health care may help to focus the development of new diagnostic technology.

Measurement of human myocardial perfusion by double-gated flow alternating inversion recovery EPI.

This paper presents a flow-sensitive alternating inversion recovery (FAIR) method for measuring human myocardial perfusion at 1.5 T. Slice-selective/non-selective IR images were collected using a double-gated IR echoplanar imaging sequence. Myocardial perfusion was calculated after T1 fitting and extrapolation of the mean signal difference SI(Sel - SI(NSel). The accuracy of the method was tested in a porcine model using graded intravenous adenosine dose challenge. Comparison with radiolabeled microsphere measurements showed a good correlation (r = 0.84; mean error = 20%, n = 6) over the range of flows tested (0.9-7 ml/g/min). Applied in humans, this method allowed for the measurement of resting myocardial flow (1.04+/-0.37 ml/g/min, n = 11). The noise in our human measurements (SE(flow) = 0.2 ml/g/min) appears to come primarily from residual respiratory motion. Although the current signal-to-noise ratio limits our ability to measure small fluctuations in resting flow accurately, the results indicate that this noninvasive method has great promise for the quantitative assessment of myocardial flow reserve in humans.

Preclinical evaluation and phase I clinical trial of a 99mTc-labeled synthetic polymer used in blood pool imaging.

OBJECTIVE: To obtain initial data on the safety and efficacy of a novel polymeric, synthetic blood pool contrast agent [O-monomethoxypoly(ethylene glycol)-O'succinyl]poly(N-epsilon-L-lysyl [99mTc]diethylenetriamine pentaacetate monoamide, we performed a preclinical evaluation and phase 1 clinical trial under an investigator-sponsored investigational new drug application. MATERIALS AND METHODS: Methoxypoly(ethylene glycol)ethylenetriaminopentaacetic acid was formulated into a kit containing the polymer, stannous chloride, and a buffer. Kits were stored in frozen form for subsequent labeling with technetium-99m. Acute and subacute toxicity studies were carried out in rats and rabbits. Healthy human volunteers (n = 6) were then enrolled in a prospective, open-label phase 1 clinical study. RESULTS: Animal studies showed no signs of acute or subacute toxicity at doses 280 times the proposed dose for humans. In the clinical trial with humans, no significant abnormalities of laboratory values, ECG findings, or hemodynamic parameters were seen. One volunteer experienced facial flushing and palpitations. Four volunteers showed typical blood pool biodistribution, with a blood half-life of 20.6 +/- 2.3 hr. At 24 hr after administration, 22.1% +/- 2.5% of the injected dose had been excreted through the kidneys. Two other volunteers showed a different biodistribution (primarily to liver and spleen), presumably associated with labeling instability. CONCLUSION: Synthetic methoxypoly(ethylene glycol)-grafted polymers can have long circulation times in humans. Pharmaceuticals based on such polymers are expected to have clinical applications in cardiovascular imaging, gastrointestinal bleeding studies, and capillary leak imaging.

The patient's role in rheumatology care.

This article reviews narrative and empiric studies in rheumatology and related literature to explicate the patient's role in rheumatology care. In contrast to early conceptualizations, such as Parsons' sick role that emphasized compliance, current literature describes chronic disease patients as active participants in their care, rather than passive recipients of care. Active patients roles include participant in shared decision making, self-manager, and help and information seeker. All of these roles are colored by the individual's need to preserve a personally defined acceptable lifestyle. Suggestions for strategies that physicians and health professionals can use to engage and support these essential patient roles are also reviewed.

Imaging perfusion deficits in ischemic heart disease with susceptibility-enhanced T2-weighted MRI: preliminary human studies.

AIM: This feasibility study explores relative myocardial perfusion characterization with an investigational T2/T2 contrast agent. METHODS: Dysprosium-DTPA bis (methylamide) was administered peripherally in six patients with thallium defects. Rest and stress multi-section, gated, T2-weighted images were acquired with a 1.5 T echo-planar imager. Change in transverse relaxation rate was calculated in four segments for each subject. RESULTS: Magnetic resonance (MR) identified five of five instances of ischemia or infarction, at a dose of agent (0.25 mmol/kg) that was comparable to that currently used with clinically approved gadolinium agents. Injection at twice this dose resulted in saturation of the signal change, and the one ischemic segment corresponding to the higher dose was not identified by MR. MR was negative in two segments which, on final diagnosis, were determined to manifest thallium attenuation artifact. CONCLUSION: MR perfusion imaging with high susceptibility agents has the potential to characterize myocardial perfusion deficits.

Contrast-to-noise ratio in functional MRI of relative cerebral blood volume with sprodiamide injection.

The purpose of this study was to investigate the dependence of contrast-to-noise ratio (CNR) on the dose and rate of sprodiamide injection in magnetic resonance relative cerebral blood volume (rCBV) imaging. rCBV maps for 35 normal volunteers were constructed from dynamic MR image sets acquired with echo-planar spin-echo imaging after intravenous injection of sprodiamide. Doses of .1, .2, and .3 mmol/kg, at rates of 2 ml/second and 5 ml/second, were tested. CNRs and blood/volume ratios of gray to white matter were computed. CNR depended on dose (P < .0001) but was independent of injection rate (P < .69). rCBV ratios of gray to white matter were dose independent (P < .38) and rate independent (P < .97). The dependence of CNR on dose, but not injection rate, has practical implications in optimal protocol design. The independence of gray/white ratios supports the theory underlying the generation of rCBV maps.

Silicone gel-filled breast implants in women: findings at H-1 MR spectroscopy.

PURPOSE: To evaluate, at hydrogen-1 magnetic resonance (MR) spectroscopy, the effect of implantation time, implant status, and implant removal on the amount of silicone in the liver in women with silicone gel-filled breast prostheses. MATERIALS AND METHODS: The study population included 55 women (39 patients with silicone gel-filled prostheses and seven from whom implants had been removed, and nine control subjects [eight with no implant and one with saline-filled implants]). Stimulated-echo acquisition mode, or STEAM, H-1 MR spectroscopy was performed to determine the concentration of silicone in the liver. Implant status at the time of spectroscopy was diagnosed at MR imaging. RESULTS: Twenty of 39 (51%) women with implants had ruptured prostheses. Resonances associated with the presence of silicone and partially hydrolyzed silicone (0.3 to -0.8 ppm with respect to water at 4.7 ppm) and other resonances that are not yet assigned (-2 to -5 ppm) were detected in 27 (69%) of the 39 women (17 with ruptured implants). Relative signal intensities of the silicone species detected in the liver in these women were found to vary substantially and were not correlated with the status of the implants (P > .70). Silicone resonances were not detected in the livers in the nine control subjects. After implant removal, no resonances between 0.3 and -0.8 ppm were observed in six of seven women, but silicone-related peaks were still detectable in the region of -2 to -5 ppm. CONCLUSION: Proton MR spectra obtained in the liver of women with silicone gel-filled breast implants helped measure silicone exposure.

Enhanced resolution of proton NMR spectra of malignant lymph nodes using magic-angle spinning.

Proton NMR spectroscopy has proven useful in the detection of cancer in lymph node tissue. However, due to the high fat content of this type of tissue, 2D 1H COSY measurements (requiring acquisition times of 4-5 h or longer) are necessary to obtain the spectral information necessary for diagnosis. T2-filtered proton magic-angle spinning (MAS) NMR spectroscopy provides 1D spectra of lymph nodes in approximately 20 min with sufficient spectral resolution allowing for identification of changes in cellular chemistry due to the presence of malignant cells. MAS data from lymph nodes of five control and six rats with mammary adenocarcinoma (R13762) demonstrated increases in the signal intensity of resonances associated primarily with lactate (delta = 4.12 ppm) P < 0.0004, creatines/lysine (delta = 3.04 ppm) P < 0.0032, and glutamate/ glutamine (delta = 2.36 ppm) P < 0.0002 in metastatic compared with normal lymph nodes. The infiltration of lymph nodes by malignant cells is an important prognostic factor for many cancers. The rapid assessment of node tissue without the introduction of sampling errors (inherent in currently employed histological procedures) would allow postoperative therapy decisions to be made more efficiently.

Meeting the needs of people with arthritis: quality of life programs of the Arthritis Foundation.

The Arthritis Foundation's Quality of Life Action Plan (Brady et al., 1993) is a strategic planning document that provides direction for service and education initiatives through the year 2000. This plan is a guide for the fulfillment of the quality of life aspect of the Arthritis Foundation's Mission Statement: "To support research to find the cure for and prevention of arthritis and to improve the quality of life for those affected by arthritis." The plan is based on documented needs and challenges that affect the quality of life of people with arthritis, with a focus on physical, psychosocial, and economic issues. This article provides a review of these issues and describes the types of services that the Arthritis Foundation provides to help people with arthritis effectively deal with these problems.

Myocardial intensity changes associated with flow stimulation in blood oxygenation sensitive magnetic resonance imaging.

Functional magnetic resonance imaging exploits deoxygenated blood as an endogenous source for contrast in assessing local changes in tissue perfusion. Intrinsic changes in myocardial signal intensity were measured during dipyridamole induced coronary vasodilatation with T2*-weighted echo planar MRI in healthy volunteers. Concurrently, changes in flow velocity in the left anterior descending coronary artery were measured using a time-of-flight method. Dipyridamole infusion produced 14 +/- 6% increase in myocardial signal intensity (n = 7). Temporal profile of the myocardial signal intensity changes correlated well with the augmentation of coronary flow velocity. The data are consistent with the concept that changes in myocardial deoxyhemoglobin content due to altered flow result in changes in magnetic susceptibility that can be detected on T2*-weighted MR images.

Magnetically labeled secretin retains receptor affinity to pancreas acinar cells.

Previously, we have developed a colloidal dextran-stabilized monocrystalline iron oxide nanocompound (MION-46) as a magnetic label for magnetic resonance imaging (MRI). In an effort to use this magnetic label to visualize pancreatic receptor function by MRI in vivo, we investigated the potential of secretin as a vector molecule. Secretin receptors, abundant on exocrine pancreas cells, recognize secretin through its amidated carboxyl terminal. In order to conjugate secretin to MION, we utilized the specific interaction between biotin and streptavidin, since direct conjugation of human secretin to MION has previously resulted in low yields and low affinity of the conjugate (unpublished results). Initially, we biotinylated the N-terminal primary amino group of secretin (60% yield). In a separate step, streptavidin (SA) was immobilized onto the surface dextran molecules of MION (79% yield) by reductive amination. Each secretin molecule was conjugated to one biotin molecule and each MION particle to an average of two SA molecules. The biotinylated secretin was then conjugated to MION through the biotin-streptavidin interaction (90% yield). The secretin-biotin-streptavidin-MION construct thus contained approximately two secretin molecules per MION. An in vitro competitive binding assay of pancreatic acinar cells demonstrated that the magnetically labeled secretin retained affinity to the secretin receptors. In vivo distribution studies in rats showed a significantly higher pancreatic accumulation of the secretin-biotin-streptavidin-MION construct as compared to the control group that had received unmodified MION. Our data indicate that bioactive peptides can be attached to dextran-coated iron oxide particles through the biotin-streptavidin interaction while retaining receptor affinity. Such target-specific agents have potential use in MR imaging to probe for a variety of receptor systems.

An adduct of cis-diamminedichloroplatinum(II) and poly(ethylene glycol)poly(L-lysine)-succinate: synthesis and cytotoxic properties.

A noncovalent adduct of the antineoplastic drug cis-diamminedichloroplatinum (cDDP) and a biocompatible graft copolymer of poly(L-lysine) and methylpoly(ethylene glycol) succinate is described. Upon incubation of cDDP with [O-methylpoly(ethylene glycol)-O'-succinyl]-N- epsilon-poly(L-lysine)n-N-epsilon-succinate, n = 250-270, highly soluble, long circulating adducts were formed which contained 4.3% of platinum by weight. Approximately 60% of the polymer-associated drug was released during dialysis against saline or serum albumin containing saline, with a half-time of release of 63 h. The adducts showed a pronounced antineoplastic effect in BT-20 human adenocarcinoma cell cultures. In cell proliferation assays, the concentration of half-inhibition of [3H]thymidine uptake was 0.9 +/- 0.2 microM for the drug-copolymer adduct compared to 0.3 +/- 0.1 microM for free cDDP. The adduct showed a long blood half-life (ca. 14 h in rats) and accumulated in experimental mammary adenocarcinomas at 2.5-3.5% injected dose per gram of tissue. A control adduct of cDDP with the backbone portion of the copolymer, poly(L-lysine)-N-epsilon-succinate, had a short half-life in the bloodstream (ca. 30 min) and low accumulation (0.5% injected dose per gram) in tumor. A dual therapeutical effect of methylpoly(ethylene glycol)succinylpoly(L-lysine)-succinate as a carrier of cDDP is suggested: (1) as a carrier for systemic release of the active drug from the macromolecule while it circulates in the bloodstream and (2) as a carrier for on-site delivery which results from the release of the drug in the tumor as a consequence of accumulation of the copolymer in the tumor.