High-frequency subharmonic pulsed-wave Doppler and color flow imaging of microbubble contrast agents.

A recent study has shown the feasibility of subharmonic (SH) flow imaging at a transmit frequency of 20 MHz. This paper builds on these results by examining the performance of SH flow imaging as a function of transmit pressure. Further, we also investigate the feasibility of SH pulsed-wave Doppler (PWD) imaging. In vitro flow experiments were performed with a 1-mm-diameter wall-less vessel cryogel phantom using the ultrasound contrast agent Definity and an imaging frequency of 20 MHz. The phantom results show that there is an identifiable pressure range where accurate flow velocity and power estimates can be made with SH imaging at 10 MHz (SH10), above which velocity estimates are biased by radiation force effects and unstable bubble behavior, and below which velocity and power estimates are degraded by poor SNR. In vivo validation of SH PWD was performed in an arteriole of a rabbit ear, and blood velocity estimates compared well with fundamental (F20) mode PWD. The ability to suppress tissue signals using SH signals may enable the use of higher frame rates and improve sensitivity to microvascular flow or slow velocities near large vessel walls by reducing or eliminating the need for clutter filters.

In vitro characterization of the subharmonic ultrasound signal from Definity microbubbles at high frequencies.

Ultrasound microbubble contrast agents have been demonstrated to scatter subharmonic energy at one-half the driving frequency. At ultrasound frequencies in the 20-40 MHz range, the subharmonic offers the potential to differentiate the blood in the microcirculation from the surrounding tissue. It is unknown whether current contrast agents, manufactured to be resonant between 2 and 12 MHz, are ideal for subharmonic imaging at higher frequencies. We performed numerical simulations of the Keller-Miksis model for the behavior of a single bubble and experimental investigations of Definity microbubbles in water. The results supported the hypothesis that off-resonant bubbles, excited at their second harmonic, may be primarily responsible for the observed subharmonic energy. For frequencies between 20 and 32 MHz and 32 and 40 MHz, the optimal bubble diameters for the generation of subharmonics in vitro were determined experimentally to be 1.2-5 microm and less than 1.2 microm, respectively. Definity may be a suitable ultrasound contrast agent for subharmonic imaging at 20 MHz with peak-negative pressures between 380 and 590 kPa and pulses greater than or equal to four cycles in duration.

Model for the ultrasound reflection from micro-beads and cells distributed in layers on a uniform surface.

A model predicting the reflection of ultrasound from multiple layers of small scattering spheres is developed. Predictions of the reflection coefficient, which takes into account the interferences between the different sphere layers, are compared to measurements performed in the 10-80 MHz and 15-35 MHz frequency range with layers of glass beads and spherical acute myeloid leukemia (AML) cells, respectively. For both types of scatterers, the reflection coefficient increases as a function of their density on the surface for less than three superimposed layers, at which point it saturates at 0.38 for glass beads and 0.02 for AML cells. Above three layers, oscillations of the reflection coefficient due to constructive or destructive interference between layers are observed experimentally and are accurately predicted by the model. The use of such a model could lead to a better understanding of the structures observed in layered tissue images.

A new ultrasound instrument for in vivo microimaging of mice.

We report here on the design and evaluation of the first high-frequency ultrasound (US) imaging system specifically designed for microimaging of the mouse. High-frequency US or US biomicroscopy (UBM) has the advantage of low cost, rapid imaging speed, portability and high resolution. In combination with the ability to provide functional information on blood flow, UBM provides a powerful method for the investigation of development and disease models. The new UBM imaging system is demonstrated for mouse development from day 5.5 of embryogenesis through to the adult mouse. At a frequency of 40 MHz, the resolution voxel of the new mouse scanner measures 57 microm x 57 microm x 40 microm. Duplex Doppler provides blood velocity sensitivity to the mm per s range, consistent with flow in the microcirculation, and can readily detect blood flow in the embryonic mouse heart, aorta, liver and placenta. Noninvasive UBM assessment of development shows striking similarity to invasive atlases of mouse anatomy. The most detailed noninvasive in vivo images of mouse embryonic development achieved using any imaging method are presented.

Assessment of rat articular cartilage maturation using 50-MHz quantitative ultrasonography.

OBJECTIVE: The objective was to assess the relationship between maturation-related structural changes of articular cartilage and variations of acoustic parameters estimated using high frequency ultrasonography. DESIGN: Patellae taken from 48 immature Wistar male rats and divided into six age groups (from five to 11 weeks old) were explored in vitro using 50-MHz scanning acoustic microscopy, then assessed by histology for the analysis of the cartilage cell distribution and fibrillar collagen organization. The variation of cartilage proteoglycan and collagen content with age was evaluated. Thickness measurements performed on both B-scan images and histologic sections were compared. Ultrasonic radiofrequency signals reflected by the cartilage surface and backscattered from its internal matrix were processed to estimate the integrated reflection coefficient (IRC) and apparent integrated backscatter (AIB). RESULTS: One-way ANOVA indicated that acoustic parameters and thickness change significantly (P < 0.05) as the animal matures because of age-related changes in cartilage composition and morphology. A moderate correlation was found between IRC and the animal age. The parameter decreased slightly but significantly over time. However, a good correlation was observed between the rat age and the AIB, which decreased significantly over time. The parameter variation was mostly related to the changes in collagen fiber orientation, and/or to a change in cell size, density and organization. CONCLUSIONS: Current results indicate that acoustic properties of cartilage are affected by maturation-related cartilage changes. This suggests that high frequency ultrasonography may serve as a useful means for the investigation of cartilage matrix structural changes occurring under various clinical circumstances, like those observed during osteoarthritis, and for the evaluation of the efficacy of specific therapeutics.

Comparison of psychosocial adaptation of advanced stage Hodgkin's disease and acute leukemia survivors. Cancer and Leukemia Group B.

BACKGROUND: The purpose of this study was to compare the long-term psychosocial adaptation of Hodgkin's disease and adult acute leukemia survivors. PATIENTS AND METHODS: Two hundred seventy-three Hodgkin's disease (HD) and 206 adult acute leukemia (AL) survivors were interviewed by telephone concerning their psychosocial adjustment and problems they attributed to having been treated for cancer, using identical research procedures and a common set of instruments. The following measures were used: Psychosocial Adjustment to Illness Scale (PAIS); Brief Symptom Inventory (BSI); current Conditioned Nausea and Vomiting triggered by treatment-related stimuli (CNVI); Indices of Employment, Insurance and Sexual Problems Attributed to Cancer; Negative Socioeconomic Impact of Cancer Index (NSI). All participants had been treated on one of nine Hodgkin's disease or 13 acute leukemia Cancer and Leukemia Group B (CALGB) clinical trials from 1966-1988, and had been off treatment for one year or more (mean years: HD = 5.9; AL = 5.6). RESULTS: HD survivors' risk of having a high distress score on the BSI was almost twice that found for AL survivors (odds ratio = 1.90), with 21% of HD vs. 14% of AL survivors (P < 0.05) having scores that were 1.5 standard deviations above the norm, suggestive of a possible psychiatric disorder. HD survivors reported greater fatigue (POMS Fatigue, P = 0.01; Vigor Subscales, P = 0.001), greater conditioned nausea (CNVI, P < 0.05), greater impact of cancer on their family life (PAIS Domestic Environment, P = 0.004) and poorer sexual functioning (PAIS Sexual Relationships, P = 0.0001), than AL survivors. CONCLUSIONS: Treatment-related issues may have placed HD survivors at a greater risk for problems in long-term adaptation than AL survivors.

Evaluation of acoustical parameter sensitivity to age-related and osteoarthritic changes in articular cartilage using 50-MHz ultrasound.

The current study reports the sensitivity of acoustical parameters estimated at high frequency to the osteoarthritic morphological and structural changes in patellar cartilage in rat knees. Osteoarthritis (OA) was induced by a single intra-articular injection of mono-iodo-acetic acid in right knees. OA patellas and their contralateral controls were excised at regular intervals after injection and were examined in vitro with a scanning acoustical microscope operating with a poly(vinylidene di-fluoride) (PVDF) 80-MHz focused transducer. Cartilage thickness was estimated using B-scan images. The quantitative analysis of the radiofrequency signal backscattered by the cartilage was performed using integrated reflection coefficient (IRC) and apparent integrated backscatter (AIB), which were estimated in the 20-60-MHz frequency range. One week after injection, a cartilage thickness decrease was detected (-6%, on average) that preceded the significant hypertrophy (20.1%) that occurred 2 weeks after injection and could be due to tissue repair. From 1 week to 3 weeks after injection, the IRC of OA patellas was significantly lower than that of control patellas. The IRC difference increased with time from -3.3 +/- 2.4 dB at 1 week to -8.4 +/- 1.7 dB at 3 weeks. An AIB decrease was observed with time for both OA and control patellas (-2.9 to -4.2 dB per week). An AIB difference between OA and control patellas was detected from 1 week to 3 weeks after injection. This difference decreased with time. IRC variation reflects a change in acoustical impedance of the superficial layer of the cartilage and could be linked to a change in constituent content and/or to a disruption of fibers of the collagen network that led to the fibrillation of the cartilage surface. AIB variation reflects a change in shape, size and/or density of the scatterers and could be related to changes in the constituent content and in the organization of the matrix in the internal layer of the cartilage. IRC and AIB could provide information about the structural modifications of the cartilage due to osteoarthritis or to cartilage maturation.

Automatic three-dimensional reconstruction and characterization of articular cartilage from high-resolution ultrasound acquisitions.

Three-dimensional (3D) high-resolution ultrasonography has proved to be useful for in vitro assessment of cartilage remodeling due to osteoarthritis. The diagnosis is performed by computation of the mean thickness of the cartilage, which reveals hypertrophy or thinning, and by 3D reconstruction of the data, which provides essential information about the size, extent, and localization of the lesion. In both cases, preliminary segmention of the cartilage is necessary. This article proposes an algorithm for automatic segmentation of the cartilage from 3D ultrasonic acquisitions of the rat patella, which includes the detection of the cartilage surface and the cartilage/bone interface. The method was designed on the assumption of regularity and smoothness of the interfaces. The use of a global threshold was sufficient to separate the patella area from the background. The cartilage/bone interface was detected by selection of regions of interest (ROIs) encompassing the interface, followed by the detection of the interface within these ROIs using the graph theory. The method was applied to 162 samples. The detection accuracy was judged to be very good or good in 99% of the cases for the cartilage surface and in 86% of the cases for the cartilage/bone interface. The mean cartilage thickness value in the central part of the patella obtained from the automatic detection method was compared to that obtained manually. The coefficient of correlation between the two measurements was 0.92. These results show that our method is reliable. Thus, fast processing of a large number of acquisitions and a more complete analysis of the cartilage surface become possible.

Which environmental variables are related to the onset of seasonal affective disorder?

The regular fall-winter onset of seasonal affective disorder is believed to be related to seasonal changes in the environment. However, the high correlation among various environmental variables has made it difficult to distinguish which ones may play a causal role. Photoperiod should explain variations in onset risk across both latitude and day of the year because it varies as a function of only these 2 factors. In Study 1, the authors found this to be the case using data from 5 locations. Environmental factors that vary from year to year should explain variations in onset risk across both time of year and actual year. In Study 2, the authors examined data from 7 years at 1 location and failed to find evidence of this effect for daily hours of sunshine, mean daily temperature, and total daily radiation. Findings support photoperiod as being related to the onset of seasonal affective disorder.

Assessment of articular cartilage and subchondral bone: subtle and progressive changes in experimental osteoarthritis using 50 MHz echography in vitro.

The main objectives of this work were to demonstrate the potential of 50 MHz echography for assessing initial and progressive morphological and structural changes of articular cartilage and bone developed in an experimental model of osteoarthritis (OA). Degenerative lesions were induced in rat knees by the unilateral intra-articular injection of a 3 mg dose of mono-iodo-acetic acid. To assess the lesion progression, the animals (n = 30) were sacrificed at different time intervals up to 8 weeks after the injection. Three-dimensional echographic data were acquired in vitro on patellar cartilage and bone at various stages of the remodeling process using a scanning ultrasound microscope. Changes involving the OA cartilage characteristics are discussed relative to those of the contralateral control joint which received a placebo. Images of control cartilage showed a smooth hyperechoic articular surface and an echoic matrix. The cartilage thickness was 266 +/- 44 microns (mean +/- SD) in the central region of the tissue. The precision of ultrasonic thickness measurements was better than 1.3%. First changes in cartilage internal structure and subchondral bone appeared on ultrasound images 3 days after the injection and were even more evident by day 7. They resulted in a slight thinning of the cartilage, a 30% increase of its internal structure echogenicity, and the appearance of echoic zones in subchondral bone. Histologic findings confirmed chondrocyte depletion and degeneration, decrease of matrix proteoglycans, and fibrovascular connective tissue proliferation at the subchondral plate. Progressive and severe lesions at both bone and cartilage surface and internal structure were assessed and correlated to histologic features. These results show that high resolution echography is sensitive to subtle and progressive osteochondral remodeling. This technique has the potential to be used for intra-articular quantitative imaging and assessment of early changes in bone and cartilage structure associated with natural human disease.

Comparison of psychosocial adaptation and sexual function of survivors of advanced Hodgkin disease treated by MOPP, ABVD, or MOPP alternating with ABVD.

BACKGROUND: Survivors of advanced Hodgkin disease, who were assigned randomly to treatment by mechlorethamine, vincristine, procarbazine, and prednisone (MOPP); doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); or MOPP alternating with ABVD in a clinical trial of the Cancer and Leukemia Group B (protocol 8251), were compared in terms of their psychosocial adaptation and psychosexual function an average of 2.2 years after completion of treatment (range, 1-5 years). The study was undertaken to determine if there were differences among treatments in these functional areas as a consequence of differential long-term gonadal damage in the three regimens. METHODS: Ninety-three disease-free survivors of advanced Hodgkin disease (56 men and 37 women) were studied (a minimum of 1 year after completion of treatment) by an interview conducted over the telephone. Standardized measures were used to assess their psychologic, sexual, family, and vocational functioning, including the following tests: the Psychosocial Adjustment to Illness Scale--Self Report, the Brief Symptom Inventory, the Profile of Mood States, and the Impact of Event Scale. RESULTS: Contrary to expectation, no statistically significant differences in survivors' psychosocial adaptation or psychosexual function were found by treatment arm. Infertility (based on survivors' reports of medical test results and perceptions) and lower income 1 year before the diagnosis of cancer were significant predictors of poorer adjustment. Most survivors reported a range of problems that they attributed to having had cancer: 35%, proven or perceived infertility; 24%, sexual problems; 31%, health and life insurance problems; 26%, a negative socioeconomic effect; and 51%, conditioned nausea, associated with visual or olfactory reminders of chemotherapy. CONCLUSIONS: No significant long-term advantage in psychosocial adaptation or psychosexual function was found for survivors of Hodgkin disease treated by the less gonadally toxic ABVD regimen 1 to 5 years after completion of treatment.

Hodgkin disease survivors at increased risk for problems in psychosocial adaptation. The Cancer and Leukemia Group B.

BACKGROUND: The long-term psychosocial adaptations of 273 survivors of advanced Hodgkin disease were assessed to determine the nature and extent of problems experienced and to identify those at high risk for maladaptation. METHODS: Hodgkin disease survivors were identified who initially had been treated in clinical trials within the Cancer and Leukemia Group B from 1966 to 1986, were currently disease free, and had completed treatment for a minimum of 1 year. All survivors had advanced Hodgkin disease (with disease diagnosed at a mean age of 28 years). Survivors were at a mean age of 37 years at the time of interview (6.3 years after treatment completion), and 60% were male. Survivors were interviewed over the telephone 7-10 days after questionnaires were mailed to them concerning their psychological, social, vocational, and sexual functioning. RESULTS: Psychological distress was found to be elevated by one standard deviation (SD) above that of healthy subjects on the Brief Symptom Inventory, and 22% met the criterion suggested for a psychiatric diagnosis. In addition, the following problems were reported by survivors to be a consequence of having had Hodgkin disease: denial of life (31%) and health (22%) insurance, sexual problems (37%), conditioned nausea in response to reminders of chemotherapy (39%), and a negative socioeconomic effect (36%). Survivors found to be at high risk for maladaptation were: men earning less than $15,000 per year or who were currently unemployed; unmarried individuals; those with serious illnesses since treatment completion; and those who were less educated. CONCLUSIONS: These findings suggest that including a routine assessment of these factors would help to target survivors in need of additional evaluation and treatment.

Quality of life assessment of Hodgkin's disease survivors: a model for cooperative clinical trials.

With the growing number of patients surviving cancer, there has been an increasing concern with their long-term adaptation. Given the large number of Hodgkin's disease survivors, it was possible to conduct a study of their psychosocial adaptation. Two hundred seventy-three survivors of advanced Hodgkin's disease were interviewed over the telephone concerning the impact of cancer upon their lives, in terms of their psychological, social, and sexual functioning. The level of psychological distress was elevated by one standard deviation above normal on the Brief Symptom Inventory (BSI), for both men and women. Survivors in greater distress reported more problems in other areas of functioning, including sexual, social, vocational, and persistent conditioned nausea.