A tutorial on ultrasonic physics and imaging techniques.

Ultrasound is a widely used modality for both therapy and diagnosis in medicine and biology. Currently, in the field of medical diagnosis, ultrasound is responsible for about one in five of all diagnostic images. The physical characteristics of medical ultrasound, along with its behaviour as it interacts with biological tissues, are described in this tutorial. The role of ultrasound in therapeutic and diagnostic applications is briefly described. In view of the importance of ultrasound as a medical imaging modality, the basic technological building blocks utilized in diagnostic ultrasound scanners are also described. Many of these topics are the subjects of other papers in this special issue where they are dealt with in more detail.

Sonoporation, drug delivery, and gene therapy.

Ultrasound is a very effective modality for drug delivery and gene therapy because energy that is non-invasively transmitted through the skin can be focused deeply into the human body in a specific location and employed to release drugs at that site. Ultrasound cavitation, enhanced by injected microbubbles, perturbs cell membrane structures to cause sonoporation and increases the permeability to bioactive materials. Cavitation events also increase the rate of drug transport in general by augmenting the slow diffusion process with convective transport processes. Drugs and genes can be incorporated into microbubbles, which in turn can target a specific disease site using ligands such as the antibody. Drugs can be released ultrasonically from microbubbles that are sufficiently robust to circulate in the blood and retain their cargo of drugs until they enter an insonated volume of tissue. Local drug delivery ensures sufficient drug concentration at the diseased region while limiting toxicity for healthy tissues. Ultrasound-mediated gene delivery has been applied to heart, blood vessel, lung, kidney, muscle, brain, and tumour with enhanced gene transfection efficiency, which depends on the ultrasonic parameters such as acoustic pressure, pulse length, duty cycle, repetition rate, and exposure duration, as well as microbubble properties such as size, gas species, shell material, interfacial tension, and surface rigidity. Microbubble-augmented sonothrombolysis can be enhanced further by using targeting microbubbles.

Automated quantitative volumetric breast ultrasound data-acquisition system.

This paper describes the development and initial testing of an automated ultrasound imaging technique to acquire quantitative volumetric breast data; the clinical application being breast cancer diagnosis and management. A novel mechanical scanner has been designed and constructed to constrain the breast tissue without compromising the image, to acquire images of the majority of the breast using a conventional B-mode scanner and to maintain patient comfort. An algorithm to improve upon simple depth-dependent amplification by compensating for tissue-dependent attenuation is applied to the images, making the grey-scale values represent local scattering properties more closely. Registration techniques have been developed to correct for geometric errors arising in the data set because of tissue movement and variations in speed of sound in the tissues. The data sets are reconstructed into volumes and viewed interactively. A pilot study of seven patients was performed and selected results are presented to illustrate lesion features. The automated scan reduces operator-dependence, provides clear information on the 3-D tissue boundaries and provides a full record for monitoring or surgical planning.

The 'RITE' use of the Fricke flap in periorbital reconstruction.

PURPOSE: To revisit an important but outmoded periorbital reconstructive technique. We present cases to illustrate the usefulness of the Fricke flap and describe a method of rapid intraoperative tissue expansion (RITE), which can enhance the applicability and effectiveness of the Fricke flap. A comparison between those cases performed with and without adjunctive RITE was not made due to the low numbers available. METHODS: A retrospective review of clinical cases. RESULTS: A total of 20 cases in which the Fricke flap was used for periorbital reconstruction were reviewed. The mean patient age was 64.7 years; the male-to-female ratio was 1:1. The patient follow-up ranged from 1 to 8 years with a mean of 4.2 years. The most common cause (65%) of periorbital defect was excision of eyelid malignancy. Necrosis of the terminal segment of the flap requiring further surgical intervention occurred in 10% (2/20). In both of these cases, the surgeons were trainees, with the complications being due to poor surgical technique. In the first case, the flap base was too narrow and in the second case, the distal end of the flap was thinned excessively. The functional result was excellent in 10/20 (50%), good in 5/20 (25%), fair in 3/20 (15%), and poor in 2/20 (10%). The cosmetic result was excellent in 3/20 (15%), good in 12/20 (60%), fair in 3/20 (15%), and poor in 2/20 (10%). CONCLUSION: The Fricke flap is an important and, in selected cases, an indispensable technique in periorbital reconstruction.

High-frequency ultrasound imaging of the intervertebral disc.

In vitro investigation of the detailed structure of the intervertebral disc has been reliant upon microdissection and histological techniques. However, these techniques are laborious and destructive; the latter aspect is important because it precludes repetitive testing of the disc during in vitro experimentation. The aim of the present study was to investigate the potential of using scanning acoustic microscopy (SAM) to image the detailed structure of the intact disc. A mechanically scanned 46-MHz transducer operating in pulse-echo mode was used to obtain images of porcine coccygeal and lumbar discs; scanned regions-of-interest (ROIs) were marked using permanent dye and small surface cuts, respectively. SAM images were compared with corresponding images obtained using conventional histological techniques. The annulus fibrosus was characterised by alternate light and dark bands; the former represent the boundary between adjacent lamellae. Lamellar discontinuities and pathologic abnormalities were observed in specimens. SAM is a novel, nondestructive method for detailed visualisation of the internal structure of the disc in vitro.

Continuous wave ultrasonic tomography.

As an object rotates with respect to a stationary ultrasonic beam, the scattering centers within the object return echoes that are Doppler-shifted in frequency by amounts depending on the velocities of the individual scatterers. The scattering centers that lie on a line of constant cross-range all have the same effective velocity in the direction pointing toward the transducer; therefore, the backscattered echo amplitude at any particular frequency is the line integral of the scattered radiation at the cross-range corresponding to that frequency. The amplitudes of the returned signals at other frequencies give the line integrals for the scatterers at the corresponding cross-ranges. The amplitude as a function of frequency can be interpreted as a tomographic projection. A continuum of the projections at different positions is generated while the object is rotating. A tomographic reconstruction algorithm can produce an image of the distribution of scattering centers in the insonified object from these projections. A microscanner was developed to investigate the approach of using continuous wave (CW) ultrasound for cross-sectional imaging. The resolution is limited by the target size and the ultrasonic wavelength.

Intervertebral disc structure: observation by a novel use of ultrasound imaging.

The internal structure of intervertebral discs is clinically important in the management of back pain. No current routine imaging modality is able to image disc structure satisfactorily. The aim of this work was to investigate and validate ultrasound imaging so that it might be applied to assessment of structural integrity and degree of degeneration. The optimum imaging technique was determined using a 3.5 MHz probe in one female subject. The applicability of this technique to investigate disc structure in the entire thoracolumbar spine was further investigated in 13 subjects. The optimum disc imaging technique was found to be a posterolateral approach, 1 to 2 cm lateral of the dorsal midline, that revealed structure within the disc not apparent using other approaches. It was demonstrated that posterolateral imaging introduces a smaller reproducibility error in measurements of linear dimensions close to the disc. It is possible to observe internal structure within the disc between T11 and L3 in at least 54% of individuals.

Development of a system to record cardiac output continuously in the newborn.

Intermittent recordings of Doppler flow velocity and cardiac output are of value during intensive care of the sick newborn infant but result in repeated disturbance of the child. We describe a new device for making continuous precordial recordings of Doppler flow velocity from the pulmonary artery in healthy resting newborn infants. Optimal probe siting was evaluated in six babies, and signals were found to be best when the pulmonary artery was insonated from the mid left parasternum. Continuous recordings were made in 13 other babies. Pulmonary artery velocities and, by calculation, cardiac output were measured continuously over periods ranging from 24 to 60 min. Median right ventricular output ranged widely from 148 to 246 mL x kg(-1) x min(-1). In contrast, for individual babies, the values were remarkably stable: the interquartile ranges varied from 13.2 to 29.9 mL x kg(-1) x min(-1). The simultaneous display of signal power allowed independent assessment of artifactual changes in cardiac output. This technique is feasible in healthy term infants and now requires evaluation in the intensive care setting where it may provide useful information concerning trends and short-term variability in right ventricular output.

Physiological control of splanchnic blood flow by adrenaline: studies during acute hypoglycaemia in man.

Superior mesenteric artery blood flow (SMABF) increases significantly during and after the hypoglycaemia reaction in healthy humans. To investigate the mechanisms controlling this phenomenon, SMABF and plasma catecholamines were measured in healthy human volunteers. In 10 controls, hypoglycaemia was induced by insulin infusion (2.5 m-units.min-1.kg-1). In six subjects, beta-blockade by propranolol infusion (0.7 microgram.min-1.kg-1) preceded insulin infusion and was continued throughout the study. Following the hypoglycaemia reaction, the glucose nadir was similar in both groups. In controls, increases in SMABF [42.4+/-6.1% (mean+/-S.E.M.); P<0. 001], cardiac output (34.3+/-2.3%; P<0.001) and pulse rate (from 63. 9+/-2.7 to 82.5+/-3.1 beats/min; P<0.001) occurred. Superior mesenteric artery resistance fell by 32.4+/-3.3% (P<0.001). Under beta-blockade, decreases in SMABF (34.8+/-2.9%; P<0.001) and pulse rate (from 59.5+/-0.2 to 51.8+/-2.2 beats/min; P<0.001) occurred. Superior mesenteric artery resistance increased (peak +30.8+/-12.3%; not significant). Subjects showed greater increases in adrenaline (P<0.006) and noradrenaline (P<0.022) concentrations than controls. Mesenteric hyperaemia associated with hypoglycaemia in man appears to be mediated by a beta-adrenergic mechanism that is activated by increased circulating levels of adrenaline.

Increased splanchnic blood flow after hypoglycaemia in diabetic and normal man: evidence against glucagon as a mediator.

Superior mesenteric artery blood flow increases significantly after hypoglycaemia in healthy humans. Glucagon has vasoactive properties but its role in hypoglycaemic hyperaemia is unclear. To assess this role, we studied the superior mesenteric artery blood flow response to hypoglycaemia of patients with uncomplicated Type 1 (insulin-dependent) diabetes mellitus of at least 10 years duration; a group known to have defective glucagon response to hypoglycaemia. Hypoglycaemia was induced using an intravenous infusion of soluble human insulin (2.5 m-units.min-1.kg-1) discontinued at a plasma glucose of 2.5 mmol/l. Superior mesenteric artery blood flow was measured using transcutaneous duplex Doppler ultrasound. Plasma samples were assayed for glucose, insulin, glucagon, catecholamines, growth hormone and cortisol. Plasma glucose concentration fell to a nadir of 1.8 (0.3) mmol/l in patients and 1.4 (0.1) mmol/l in controls. Plasma glucagon concentration was unchanged in patients from a baseline level of 111.7 (13.1) ng/l but rose in controls from 105 (8.5) to a peak of 239 (3.1) ng/l (P<0.001). Superior mesenteric artery blood flow increased in both groups: from 385 (29) to 921 (100) ml/min (140% increase; P<0.05) in patients and from 517 (50) to 790 (67) (53% increase; P<0.001) in controls. This study shows that patients with Type 1 diabetes have a normal splanchnic vascular hyperaemic response to hypoglycaemia despite defective glucagon counter-regulation. These results support our previous work suggesting that glucagon is not a major mediator of this response; it seems likely that circulating adrenaline is the major regulatory mechanism.

A comparison of digital retinal images and 35 mm colour transparencies in detecting and grading diabetic retinopathy.

We compared digital retinal images and 35 mm colour transparencies taken with the Canon CR5 retinal camera for the detection and grading of diabetic retinopathy in a clinical setting, in a randomized, blinded study of diabetic patients with a spectrum of severity of diabetic retinopathy. Forty patients were photographed, giving a total of 75 eyes including non-diabetic eyes as controls. Images were graded according to the validated European guidelines. There was exact agreement between grades obtained from both the 2 field 45 degrees 35 mm colour transparencies and digital images in 93.3% (70/75) of eyes, with Cohen's Kappa statistic for the comparison being 0.92. Overall, when grading from the digital images 5.3% (4/75) eyes were undergraded with three cases of sight threatening diabetic retinopathy (STDR) graded as non-sight threatening (NSTDR) (3/48, 6.3%). One eye was overgraded (1/75, 1.3%). Two of the three cases of STDR undergraded as NSTDR had small numbers of intra-retinal microvascular abnormalities (IRMA) discernible on the colour transparencies but which were not visible from the digital image. The third had multiple small cotton wool spots graded as laser photocoagulation scars from the digital images. In conclusion there is good to excellent agreement between retinopathy grades using the Canon CR5 digital retinal imaging system compared to 35 mm colour transparencies.

Thyrotropin receptor transcripts in human adipose tissue.

Thyroid associated ophthalmopathy (TAO) is generally considered to have an autoimmune pathogenesis but the target antigen has yet to be identified. It is most frequently associated with Graves' disease and there is some logic in assuming that the same antigen, the thyrotropin receptor (TSHR), is the common link. Previous studies, mostly PCR based, aimed at investigating TSHR transcripts in the orbit, have yielded conflicting results, although there is circumstantial evidence for their presence in orbital fat. In this study, we have examined adult human adipose and muscle tissues from various locations, initially by PCR and subsequently by northern blot. We obtained the expected 610bp product in normal intestinal and orbital fat but not skeletal muscle, following two rounds of PCR amplification but only when reverse transcription used a TSHR specific primer. In northern blots, despite loading all of the RNA obtained from total normal orbital fat contents, TSHR transcripts were at the limit of detection and similarly for large samples of intestinal fat. The exception was RNA obtained from TAO orbital fat, in which TSHR transcripts of 4.6 and 1.7kb were clearly visible, as in the thyroid. We conclude that normal adult adipose tissues contain low levels of TSHR transcripts. In TAO, TSHR transcripts are elevated probably due to an increased number of cells, in particular of preadipocytes in orbital adipose tissue.

Splanchnic blood flow in patients with cirrhosis and portal hypertension: investigation with duplex Doppler US.

PURPOSE: To investigate splanchnic blood flow changes in patients with hepatic cirrhosis and portal hypertension. MATERIALS AND METHODS: Duplex Doppler ultrasound (US) was used to measure blood flow in the superior mesenteric artery (SMA) and splenic artery in 20 patients with biopsy-proved cirrhosis and clinical evidence of portal hypertension, and in 20 healthy volunteers who were matched for age and sex. RESULTS: Mean SMA and splenic artery blood flow was significantly greater in the patients than in healthy subjects. Neither SMA nor splenic artery blood flow was increased in patients with normal-sized spleens; however, blood flow was significantly elevated in patients with splenomegaly. Total splanchnic blood flow in patients was also significantly elevated compared with healthy subjects. Total splanchnic blood flow in patients with normal-sized spleens was not significantly elevated compared with healthy subjects, but splanchnic flow was significantly increased in patients with splenomegaly. CONCLUSION: Blood flow is increased in the SMAs and splenic arteries of patients with cirrhosis and portal hypertension. Increased splanchnic blood flow associated with cirrhosis may occur exclusively in patients with splenomegaly.

Ultrasound quantitation of respiratory organ motion in the upper abdomen.

Organ motion can cause artefacts in abdominal imaging particularly with magnetic resonance imaging (MRI), and may often limit the diagnostic quality of an image. If spatial resolution and image quality are to improve in MRI and other imaging techniques, a more detailed understanding of organ motion is required. Despite the importance of organ motion little quantitative information is available to date. This study was the continuation of work instigated to investigate and quantify respiratory movements of upper abdominal organs for a group of healthy volunteers in order to provide the design criteria for a motion test object for use in MRI. A previous phase of the project allowed construction of a test object but refinements were needed to represent respiratory motion more closely as a consequence of the data presented in this paper. Improvements in the scanning technique and the recording procedure have revealed that, contrary to our initial findings, motion of the diaphragm and liver is predominantly in the superior-inferior (SI) direction with an average displacement (+/- SD) (quiet respiration) of 12 +/- 7 mm (range 7-28 mm) and 10 +/- 8 mm (range 5-17 mm), respectively. For some volunteers, motion of the kidneys can be complex, especially during deep inspiration. New data have been provided by this phase of the motion study on the displacement, velocity and acceleration of abdominal organs as a function of time. These data show that MRI motion artefact reduction techniques which assume that either organ displacement, velocity or acceleration are constant are only applicable during certain phases of the respiratory cycle.

A comparative study of velocity measurements in major blood vessels using magnetic resonance imaging and Doppler ultrasound.

Velocity measurements in major blood vessels were obtained in studies of volunteers using magnetic resonance imaging (MRI) and compared with Doppler ultrasound (US). The vessels studied were the abdominal aorta, superior mesenteric artery, common carotid artery, superficial femoral artery and middle cerebral artery. Using a paired t-test, no significant difference was found between velocity values estimated by MRI and US (p > 0.08). The relative advantages of each technique in radiological practice are discussed.

Quality assurance of ultrasound imaging instruments by monitoring the monitor.

Ultrasound quality assurance (QA) is a means of assuring the constant performance of an ultrasound instrument. A novel 'ultrasound image analyser' has been developed to allow objective, accurate and repeatable measurement of the image displayed on the ultrasound screen, i.e. as seen by the operator. The analyser uses a television camera/framestore combination to digitize and analyse this image. A QA scheme is described along with the procedures necessary to obtain a repeatable measurement of the image so that comparisons with earlier good images can be made. These include repositioning the camera and resetting the video display characteristics. The advantages of using the analyser over other methods are discussed. It is concluded that the analyser has distinct advantages over subjective image assessment methods and will be a valuable addition to current ultrasound QA programmes.

Splanchnic blood flow in man: evidence for mediation via a beta-adrenergic mechanism.

1. Superior mesenteric artery blood flow was examined by Doppler ultrasound in six male subjects aged 19-23 years during the infusion of saline (control), 10 and 40 ng of adrenaline min-1kg-1 for 30 min, or propranolol and 10 ng of adrenaline min-1kg-1 for 30 min, on four separate occasions. 2. Adrenaline infusion resulted in significant peak mean (SEM) rises in circulating adrenaline concentrations during the infusion period only [control, 0.20 (0.05) nmol/l; 10 ng of adrenaline min-1kg-1, 1.37 (0.29) nmol/l; 40 ng of adrenaline min-1kg-1, 3.73 (0.40) nmol/l; 10 ng of adrenaline min-1kg-1 and propranolol, 1.48 (0.16) nmol/l, P < 0.001 versus control]. These values are within the physiological range. 3. Superior mesenteric artery blood flow rose in a dose-dependent manner during the adrenaline infusions alone, but not during the infusion of adrenaline and propranolol [mean (95% confidence interval) area under the curve: control, -4.2 (-11 to +2.7)%; 10 ng of adrenaline min-1kg-1, +4 (-1 to 11.9)%; 40 ng of adrenaline min-1kg-1, +34 (+6.5 to +61.5)%; 10 ng of adrenaline min-1kg-1 and propranolol, -8.4 (-23 to +6)%]. 4. Superior mesenteric artery resistance fell during the adrenaline infusions alone and rose during the combined adrenaline and propranolol infusion [mean (SEM) area under the curve: control, 6.4 (2.7)%; 10 ng of adrenaline min-1kg-1, -2.9 (2.5)%; 40 ng of adrenaline min-1kg-1, -15 (1.4)%; 10ng of adrenaline min-1kg-1 and propranolol, 16.9 (10)%]. 5. These data suggest that splanchnic vasodilatation is mediated via a beta-adrenergic mechanism.

Evidence against a putative role for glucagon as a physiological splanchnic vasodilator in man.

1. Previous studies have suggested that glucagon in supraphysiological doses may mediate postprandial and hypoglycaemia-induced splanchnic vasodilatation in man and experimental animals. There are no reported studies investigating the role of glucagon in doses producing circulating concentrations within the physiological range. 2. Two separate studies were performed. In study 1, superior mesenteric artery blood flow was measured by Doppler ultrasound in six normal subjects during either saline or glucagon infusion at 1, 3 and 6 ng min-1kg-1, which resulted in circulating glucagon levels within the physiological range. Mean superior mesenteric artery blood flow fell during the 3 and 6 ng min-1kg-1 glucagon infusions (3 ng min-1kg-1: -31.8%, range -20 to -56% of baseline; 6 ng min-1kg-1: -20.7%, range -8 to -53% of baseline; P < 0.05). 3. In study 2, superior mesenteric artery blood flow was measured during hypoglycaemia induced by an insulin infusion in 12 normal subjects. In six of these subjects the effect of suppression of glucagon release during hypoglycaemia was assessed by pretreatment with the somatostatin analogue octreotide (0.8 microgram/kg subcutaneously) given 30 min before the insulin infusion. 4. The nadir in blood glucose concentration at the hypoglycaemic reaction was similar in both groups and glucose recovery was complete by 60 min after the hypoglycaemic reaction. Plasma catecholamine concentrations rose in both groups after the hypoglycaemic reaction. 5. Superior mesenteric artery blood flow rose at the hypoglycaemic reaction in both groups despite suppression of glucagon release with octreotide.(ABSTRACT TRUNCATED AT 250 WORDS)