Showing papers in "Radiology in 1988"

Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging.

Abstract: Intravoxel incoherent motion (IVIM) imaging is a method the authors developed to visualize microscopic motions of water. In biologic tissues, these motions include molecular diffusion and microcirculation of blood in the capillary network. IVIM images are quantified by an apparent diffusion coefficient (ADC), which integrates the effects of both diffusion and perfusion. The aim of this work was to demonstrate how much perfusion contributes to the ADC and to present a method for obtaining separate images of diffusion and perfusion. Images were obtained at 0.5 T with high-resolution multisection sequences and without the use of contrast material. Results in a phantom made of resin microspheres demonstrated the ability of the method to separately evaluate diffusion and perfusion. The method was then applied in patients with brain and bone tumors and brain ischemia. Clinical results showed significant promise of the method for tissue characterization by perfusion patterns and for functional studies in the eva...

Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging.

Abstract: The authors reviewed magnetic resonance (MR) images of 474 consecutive patients referred for lumbar spine MR imaging. Type 1 changes (decreased signal intensity on T1-weighted spin-echo images and increased signal intensity on T2-weighted images) were identified in 20 patients (4%) and type 2 (increased signal intensity on T1-weighted images and isointense or slightly increased signal intensity on T2-weighted images) in 77 patients (16%). In all cases there was evidence of associated degenerative disk disease at the level of involvement. Histopathologic sections in three cases of type 1 change demonstrated disruption and fissuring of the end plates and vascularized fibrous tissue, while in three cases of type 2 change they demonstrated yellow marrow replacement. In addition, 16 patients with end-plate changes documented with MR were studied longitudinally. Type 1 changes in five of six patients converted to a type 2 pattern in 14 months to 3 years. Type 2 changes in ten patients remained stable over a 2-3...

Human heart: tagging with MR imaging--a method for noninvasive assessment of myocardial motion.

Abstract: Specified regions of the myocardium can be labeled in magnetic resonance (MR) imaging to serve as markers during contraction. The technique is based on locally perturbing the magnetization of the myocardium with selective radio-frequency (RF) saturation of multiple, thin tag planes during diastole followed by conventional, orthogonal-plane imaging during systole. The technique was implemented on a 0.38-T imager and tested on phantoms and volunteers. In humans, tags could be seen 60-450 msec after RF saturation, thus permitting sampling of the entire contractile phase of the cardiac cycle. Tagged regions appear as hypointense stripes, and their patterns of displacement reflect intervening cardiac motion. In addition to simple translation and rotation, complex motions such as cardiac twist can be demonstrated. The effects of RF pulse angle, relaxation times, and heart rate on depiction of the tagged region are discussed.

Normal maturation of the neonatal and infant brain: MR imaging at 1.5 T.

Abstract: The pattern of normal white-matter maturation as demonstrated with high-field-strength magnetic resonance (MR) imaging was investigated. Eighty-two neurologically normal infants were examined with a 1.5-T unit with use of spin-echo T1-weighted and T2-weighted pulse sequences. The infants ranged in age from 4 days to 2 years. The images were assessed for qualitative changes of white matter relative to gray matter in 14 anatomic areas of the brain and correlated with the patient's age. The MR images showed that changes of brain maturation occur in an orderly manner, commencing in the brain stem and progressing to the cerebellum and the cerebrum. Changes caused by brain myelination were seen earlier on T1-weighted images than on T2-weighted images, possibly because of T1 shortening by the components of the developing myelin sheaths. The later changes on the T2-weighted images correlated best with the development of myelination as demonstrated with histochemical methods. T1-weighted images were most useful in the monitoring of normal brain development in the first 6-8 months of life; T2-weighted images were more useful after 6 months. The milestones in the MR appearance of normal maturation of the brain are presented. Persistent areas of long T2 relaxation times are seen superior and dorsal to the ventricular trigone in all infants examined and should not be mistaken for ischemic change.

Bone marrow imaging.

Abstract: La moelle normale, anatomie et fonction. Distribution de la moelle hematopoietique en fonction de l'âge, composition chimique. Les methodes d'imagerie: radiographie, scintigraphie TDM, RMN. Les images RMN dependent des sequences de pulsion. Choix des techniques. Pathologie. Greffes de moelle. Œdemes medullaires. Ischemies

Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging of the liver

Abstract: Superparamagnetic iron oxide (ferrite) particles were evaluated as a contrast agent for magnetic resonance (MR) imaging. In this pilot study, doses ranging from 10 to 50 mumol/kg were administered intravenously to 15 patients. Ferrite-enhanced images of the liver obtained with standard pulse sequence techniques significantly increased the number of hepatic lesions detected (P less than .01) and reduced the threshold size for detection to 3 mm (P less than .01). The improved clinical performance of ferrite-enhanced images correlated with significant increases in measured contrast-to-noise ratios (P less than .01). Degradation of superparamagnetic activity and/or clearance of ferrite from the liver was demonstrated as early as 12 hours after injection, suggesting that the lack of chronic toxicity observed in animal studies may be reproduced in humans. These initial clinical results appear to confirm extensive preclinical data indicating that ferrite administered at a dose of 20 mumol/kg has the potential to significantly improve the performance of abdominal MR imaging.

Pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy.

Abstract: Over a 10-year period, 276 pulmonary arteriovenous malformations (PAVMs) were occluded with balloon embolotherapy in 76 patients, 67 (88%) of whom had hereditary hemorrhagic telangiectasia. Eleven patients (14%) were discovered by means of family screening with measurement of arterial blood gases and chest radiography. Epistaxis, dyspnea, hemoptysis, and hemothorax occurred in 79%, 71%, 13%, and 9% of patients, respectively. Clinical histories of strokes and transient ischemic attacks were present in 18% and 37% of patients, respectively. Computed tomographic scans of 59 patients showed stroke in 36%. Sixty-five percent of PAVMs were located in the lower lobes, which correlated with the finding of more pronounced hypoxemia in the upright position. After embolotherapy, symptomatic hypoxemia was corrected, and serial values have remained constant for 5 years. Complications were minimal, and no patient required surgery. Balloon embolotherapy is effective long-term therapy for PAVMs, and family screening shou...

Fungal sinusitis: diagnosis with CT and MR imaging.

Abstract: Of 293 patients who underwent computed tomography (CT), surgery, and pathologic examination for chronic sinusitis, 25 had a diagnosis of fungal sinusitis at pathologic examination. Of these, 22 had foci of increased attenuation at CT (in four patients the mean representative CT number [Hounsfied unit] was 122.2 HU [SD, 8.2 HU]), and three did not. Of the 22, 19 patients (76%) met the CT criterion of this study (there was a 12% false-positive and a 12% false-negative diagnostic rate). Six of the 19 patients and one additional patient underwent magnetic resonance (MR) imaging, and all demonstrated remarkably hypointense signal characteristics on T2-weighted images. The findings at MR imaging therefore appear more characteristic of fungal sinusitis than the findings at CT. Furnace atomic absorption spectrometry showed increased concentrations of iron and manganese in mycetoma compared with their concentrations in bacterially infected mucus. This finding and the presence of calcium in the fungal concretion ma...

Tears of the anterior cruciate ligament and menisci of the knee: MR imaging evaluation.

Abstract: In 242 of 3,000 patients who underwent magnetic resonance (MR) imaging of the knee between September 1986 and August 1987, original MR imaging reports were compared with subsequent arthroscopic reports to determine the value of MR imaging in the evaluation of suspected meniscal and complete tears of the anterior cruciate ligament. The overall accuracy for the menisci was 93% (sensitivity, 95%; specificity, 91%) with a false-negative rate of 4.8%. For the anterior cruciate ligament the overall accuracy was 95%. T2-weighted sequences were associated with greater sensitivity, specificity, and accuracy than were T1 sequences; the false-negative rate was 0% in the T2-weighted group. MR imaging of the knee is an extremely accurate means for noninvasive assessment of the integrity of the menisci and anterior cruciate ligament, and the accuracy exceeds that usually reported for arthrography.

Breast cancer: PET imaging of estrogen receptors.

Abstract: Thirteen patients with primary breast masses were studied with positron emission tomography (PET) and 16 alpha-[fluorine-18]-fluoroestradiol-17 beta. PET images demonstrated uptake of the labeled estrogen analog at sites of primary carcinomas and in several foci of axillary lymph node metastases, as well as in one distant metastatic site. There was excellent correlation between uptake within the primary tumor measured on the PET images and the tumor estrogen-receptor concentration measured in vitro after excision (r = .96). This technique may provide an in vivo method of assessing estrogen receptors in primary and metastatic breast cancers and thus guide management of this disease with antiestrogen chemotherapy.

Vertebral bone density in children: effect of puberty.

Abstract: To determine changes in bone density during growth, trabecular vertebral density and an index of spinal cortical bone were measured with quantitative computed tomography in 101 children The children were divided by age into three groups: prepubertal, indeterminate, and pubertal Compared with prepubertal children, pubertal adolescents had significantly higher trabecular bone density and more compact bone in the spine (P less than 001) After controlling for puberty, vertebral bone density failed to correlate significantly with age, sex, weight, height, surface area, and body mass index The results indicate that bone density increases markedly during puberty

Acute appendicitis: sonographic criteria based on 250 cases.

Abstract: Two hundred and fifty consecutive patients with suspected appendicitis were examined with graded compression sonography. The initial diagnostic criterion for appendicitis was visualization of a noncompressible appendix; this was later modified to include the dimensions of the visualized appendix. The appendix was visualized in 91 of 250 patients (36%). Five adult patients with sonographically visible appendixes that were 6 mm or less in maximal diameter had either benign clinical follow-up (three patients) or a histologically normal appendix removed at surgery (two patients). However, two patients with appendixes measuring 6 mm in diameter and multiple appendicoliths had surgically confirmed acute appendicitis. Of 84 patients with visible appendixes measuring greater than 6 mm in maximal diameter, 78 had surgically confirmed acute appendicitis. In the remaining six, symptoms resolved spontaneously, and no surgery was required. In the absence of compelling clinical findings or an appendicolith, adult patients with maximal appendiceal diameters of 6 mm or less should undergo a period of close observation rather than immediate surgery. A diagnosis of appendicitis can be made in adult patients with persistent right lower quadrant pain and a visualized appendix greater than 6 mm in diameter.

Quantitative CT for determination of bone mineral density: a review

Abstract: One of the major uses of quantitative computed tomography (CT) has been the measurement of bone mineral density (BMD) at various skeletal sites. The published literature on this subject from 1974 to the present is extensive. Because many investigators and clinicians are just now starting to explore the utility of this technique, the author reviewed this literature to provide both the historic perspective and current status of BMD measurement with CT. The physical and physiologic bases of the method, accuracy, reproducibility, radiation dose, and clinical utility are all discussed.

Transient osteoporosis: transient bone marrow edema?

Abstract: Ten patients with debilitating hip or knee pain were examined with magnetic resonance (MR) imaging. All had conventional radiographs that were either normal or showed nonspecific osteopenia. Nine patients had bone scintigrams that showed focal increased radionuclide uptake in the region of the painful joint. In each case, MR images of the affected joint showed regional decreased signal intensity of the bone marrow on T1-weighted images and increased signal intensity on T2-weighted images. Biopsy results of four patients excluded ischemic necrosis and metastases. The symptoms resolved spontaneously in all cases. The ten patients were followed up for 12-36 months, and there were no recurrences. The authors believe that the findings on MR images represent a transient increase in bone marrow water content. The focal findings on scintigrams confirmed the periarticular distribution of the process and provided evidence of accompanying hyperemia and increased bone mineral metabolism. For lack of a better term and to emphasize the generic character of the condition, the authors termed this condition "the transient marrow edema syndrome."

Invasive cervical carcinoma: comparison of MR imaging and surgical findings.

Abstract: The accuracy of magnetic resonance (MR) imaging in staging invasive carcinoma of the cervix was determined retrospectively in 57 consecutive patients in whom the extent of disease was surgically confirmed. MR images were analyzed for (a) location and size of the primary tumor; (b) tumor extension to the uterine corpus, vagina, parametria, pelvic sidewall, bladder, or rectum; and (c) pelvic lymphadenopathy. The accuracy of MR imaging in determination of tumor location was 91% and for determination of tumor size within 0.5 cm, 70%. Its accuracy was 93% for vaginal extension and 88% for parametrial extension. Pelvic sidewall, bladder, and rectal involvement were accurately excluded in all patients, but the positive predictive values were 75%, 67%, and 100%, respectively. Overall, the accuracy of MR imaging in staging was 81%. MR imaging is valuable because it can accurately demonstrate tumor location, tumor size, degree of stromal penetration, and lower uterine segment involvement. It is also valuable for ruling out parametrial, pelvic sidewall, bladder, and rectal involvement.

Cerebral astrocytomas: histopathologic correlation of MR and CT contrast enhancement with stereotactic biopsy.

Abstract: Gadolinium-labeled diethylenetriaminepentaacetic acid was used as a contrast agent for stereotactic magnetic resonance (MR) imaging in six selected patients with brain tumors who underwent stereotactic biopsy. Regions of contrast enhancement demonstrated by computed tomography (CT) and MR imaging in four of the six patients correlated with areas of malignant neovascularity and endothelial proliferation within solid tumor. Radiation necrosis produced contrast enhancement indistinguishable from that of recurrent neoplasm. Isolated tumor cells within intact white matter were identified in biopsy specimens obtained outside of regions that were depicted as abnormal by contrast material-enhanced CT, as well as by precontrast and postcontrast T1- and T2-weighted MR images.

MR imaging of laser-tissue interactions.

Abstract: A new application of magnetic resonance (MR) imaging to map the spatial and temporal distribution of the effects of Nd:YAG lasers on tissues was studied. The temperature dependence of MR relaxation mechanisms and the high sensitivity of MR to changes in the mobility and distribution of tissue water make it particularly suitable for the demonstration and control of thermal energy deposition in tissues. In heterogeneous tissues, MR imaging does not follow changing temperatures directly because even in the case of reversible thermal interactions, there is a hysteresis in the dynamic relationship between MR signal intensity and temperature. Appropriate matching of the laser and MR pulse sequences can, however, optimize the detection of relatively small laser energy deposition, and reversible and irreversible tissue changes can be distinguished. There is a potential for the integration of MR imaging and lasers for three-dimensional control and monitoring of laser-tissue interactions.

Exclusion of fetal ventriculomegaly with a single measurement: the width of the lateral ventricular atrium.

Abstract: The ventricular atria in 100 healthy fetuses with gestational ages ranging from 14 to 38 menstrual weeks were evaluated and compared with those of 38 fetuses in whom ventriculomegaly had been diagnosed in utero. Axial sonograms of the brain through the atrium of the lateral ventricle demonstrated that the normal atrial diameter remained relatively constant throughout the gestational age range observed. The atrium had a mean diameter of 7.6 +/- 0.6 mm (standard deviation [SD]). Measurement of this structure can be quickly performed, is reproducible with low intra- and interobserver variation, and permits ventriculomegaly to be excluded. Atrial diameters exceeding 10 mm (above 4 SDs) suggest ventriculomegaly, with a low false-positive rate.

Peripheral nerves of the extremities: imaging with US.

Abstract: High-resolution real-time ultrasonography (US) was used to evaluate peripheral nerves of the extremities in healthy subjects and in 11 patients with a mass developed from a peripheral nerve. The normal median and ulnar nerves in the upper extremity and the normal sciatic and external popliteal nerves in the lower extremity were seen, all having an echogenic fibrillar echotexture. Pathologic findings included nine cases of benign tumor (four schwannomas, three neurofibromas, two traumatic neuromas), one of neurilemmitis, and one of tuberculoid leprosy. All lesions were hypoechoic. Three of the four schwannomas had well-defined contours, and two were associated with a typical distal sound enhancement. Neurofibromas and traumatic neuromas were less sharply delineated. Inflammatory conditions were characterized by a hypoechoic, thickened nerve. US was effective in imaging nerve masses in the extremities, and large normal nerves can now be demonstrated with high-resolution US.

Anterior cruciate ligament tears: MR imaging compared with arthroscopy and clinical tests.

Abstract: Seventy-nine magnetic resonance (MR) studies of the knee were reviewed in an evaluation of the ability of MR imaging to demonstrate arthroscopically proved anterior cruciate ligament (ACL) tears. MR findings were also compared with the findings of two commonly applied clinical tests of ACL instability: the Lachman test and the anterior drawer test. The sensitivity of MR imaging was 94% (17 of 18), compared with 78% (14 of 18) for the anterior drawer test and 89% (16 of 18) for the Lachman test. The specificity was 100% for all three. Three MR criteria were applied: irregularity or a wavy contour of the anterior margin of the ligament, high-signal-intensity change within the substance of the ligament on T2-weighted images, and discontinuity of that substance. The sagittal T2-weighted image was especially helpful, producing an "arthrographic" effect, in which the anterior margin of the ACL is outlined by high-signal-intensity joint fluid. By demonstrating ACL and other extrameniscal lesions, MR imaging may help clarify the mechanisms of knee injury.

Nonpalpable breast lesions: recommendations for biopsy based on suspicion of carcinoma at mammography.

Abstract: Carcinoma was found in 30% (119 of 400) of biopsy specimens obtained for mammographically suspicious but nonpalpable findings. The authors reviewed the mammograms of these 400 cases without knowledge of the biopsy results and placed each examination into one of four groups based on their suspicion for carcinoma: minimal (n = 82), slight (n = 91), moderate (n = 174), and high (n = 53). In 127 cases, mammograms showed either minimally suspicious calcifications (n = 33) or minimally (n = 49) or slightly (n = 45) suspicious masses. A 4.7% (six of 127) rate of carcinoma was found in these groups; five of the six cancers were in situ. Had follow-up mammography been done rather than biopsy for these 127 less suspicious lesions, it is probable that the delay in diagnosis would not have altered overall prognosis. In the remaining 273 patients, the positive predictive value of mammography for carcinoma would have risen from 30% (119 of 400) to 41% (113 of 273). The authors conclude that in the management of suspici...

Pancreatic ductal adenocarcinoma: diagnosis and staging with dynamic CT.

Abstract: The authors assessed the accuracy of dynamic computed tomography (CT) in diagnosis and staging of ductal adenocarcinoma of the pancreas and analyzed the survival rates of patients with resectable and unresectable tumors. A correct diagnosis based on CT findings was made in 159 of 174 patients (91%) with 13 false-positive (8%) and two false-negative diagnoses (1%). The 13 false-positive diagnoses highlight the need for confirmation of diagnosis with biopsy. The accuracy of staging with CT was compared with that of angiography (42 patients) and surgery (51 patients). CT was more accurate than angiography in demonstrating tumor involvement of major peripancreatic vessels. Staging criteria were reliable: No unresectable tumors based on CT findings were found to be resectable during surgery (42 patients), while only three of nine resectable tumors based on CT findings were found to be unresectable. Thus, no tumors were incorrectly staged, which would potentially deny surgery for a patient. The average survival...

Difficult thoracic lesions: CT-guided biopsy experience in 150 cases.

Abstract: Computed tomography (CT) was used to guide percutaneous fine-needle biopsy in 150 cases of difficult thoracic lesions; in 76 cases, nondiagnostic bronchoscopy (n = 62) and fluoroscopic biopsy (n = 14) had previously been performed. CT was indicated for guidance when the pulmonary or pleural lesions were small (0.3-2.5 cm); in a juxta-vascular location, either hilar or mediastinal; not seen or poorly visualized on conventional radiographs; or considered inaccessible. A diagnosis was made in 124 of 150 cases (82.7%) (107 of 124 malignant and 17 of 26 benign lesions), including 86 of 107 lung nodules (80.4%), 28 of 31 mediastinal lesions (90.3%), and ten of 12 pleural masses (83.3%). Complications included pneumothorax (n = 64), hemoptysis (n = 5), hemothorax (n = 2), and pericarditis (n = 1). The high rate of pneumothorax, its treatment, and advantages of its immediate radiologic management are discussed. Use of CT guidance considerably expands the scope of thoracic lesions amenable to percutaneous biopsy.

Stress fractures: MR imaging.

Abstract: Five cases of stress fracture were studied with high-field-strength magnetic resonance (MR) imaging. In all cases, MR images showed bandlike areas of very low signal intensity in the intramedullary space, which were continuous with the cortex. These findings corresponded in location to the sites of fracture or new bone formation noted on radiographs. Surrounding areas of decreased signal intensity in the marrow space were also consistently seen on T1-weighted images. In three cases, prominent intramedullary areas of high signal intensity were noted on T2-weighted images obtained within 3 weeks of the onset of symptoms. Juxtacortical and/or subperiosteal areas of high signal intensity were also seen on T2-weighted images in two cases. Characteristic MR findings may distinguish stress fracture from occult intraosseous fracture.

Early CT finding in cerebral infarction: obscuration of the lentiform nucleus.

Abstract: Early computed tomographic (CT) findings (scans obtained within 6 hours of the onset of stroke) were retrospectively analyzed in 25 patients with embolic cerebral infarction of the middle cerebral artery or internal carotid artery distribution, including the lentiform nucleus, diagnosed on the basis of findings at sequential CT. CT scans were analyzed for the following: (a) an obscured outline or partial disappearance of the lentiform nucleus, (b) a slight decrease in tissue density, or (c) effacement of the cortical sulci. One or more of these findings was recognized in 23 of 25 patients (92%). The first finding was noted most frequently, and it appeared earliest. Obscuration of the lentiform nucleus was thought to be an important early sign of cerebral infarction, including the lentiform nucleus.

Lymphedema: evaluation of qualitative and quantitative lymphoscintigraphy in 238 patients.

Abstract: Lymphoscintigraphy was performed in 128 patients with primary lymphedema, in 91 patients with secondary lymphedema, and in 19 healthy volunteers. A total of 457 extremities were examined. Technetium-99m-labeled human serum albumin was injected subcutaneously, and passive muscular exercise was standardized to reduce the variability of lymphatic function. The scintigrams were analyzed for visualization of lymph vessels and lymph nodes, dilatation of lymphatic vessels, existence of collateral vessels, and dermal backflow. With this qualitative interpretation alone, the diagnosis of lymphedema was established in 216 of 308 extremities (70.1%). Quantitative parameters derived from clearance data showed abnormal lymphatic function in all 308 extremities. Whereas qualitative lymphoscintigraphy allows the characterization of lymphatic morphology, quantitative lymphoscintigraphy is very accurate in detection of incipient lymphedema.

Prostate cancer: comparison of transrectal US and digital rectal examination for screening.

Abstract: The authors examined 784 self-referred men over age 60 years to compare clinical usefulness of transrectal ultrasound (US) and digital rectal examination in a screening program for prostate cancer. Biopsy was performed in 77 cases, 83% (64 of 77) for abnormalities detected with transrectal US and 38% (29 of 77) because of findings at digital examination. Twenty-two cancers were detected, 20 with transrectal US and ten at digital examination. Overall detection rate for prostate cancer with transrectal US was two times higher than that with digital examination (2.6% vs 1.3%). Sensitivity, specificity, and negative predictive value for transrectal US and digital examination were calculated for a range of prevalences (0.028-0.1543). Sensitivity was two times higher for transrectal US than for digital examination. Transrectal US demonstrated 100% (17 of 17) of tumors with the most favorable prognosis (less than or equal to 1.5 cm in diameter) compared with 41% (seven of 17) for digital examination. The authors conclude that transrectal US is more sensitive than digital examination in the detection of prostate cancer, and they advocate broader implementation and evaluation of transrectal US as a tool for early detection.

Gd-DOTA: characterization of a new paramagnetic complex

Abstract: The relaxivity, biodistribution, and toxicity of the gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA) complex were evaluated. This cyclic complex has much greater in vitro stability (10(28)) than similar noncyclic complexes such as gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) (10(23)) or gadolinium-ethylenediaminetetraacetic acid (Gd-EDTA) (10(17)). The T1 relaxivity of Gd-DOTA (meglumine salt) determined in saline and in liver tissue at 20 MHz was similar to the relaxivity of Gd-DTPA. Tissue proton relaxation enhancement (PRE) correlated closely with chemical measurement of tissue gadolinium concentration. In rats, the biodistribution of Gd-DOTA was similar to Gd-DTPA with a distribution half-life of 3 minutes and an elimination half-life of 18 minutes. The median lethal dose (LD50) in mice of Gd-DOTA was 93% higher than that of Gd-DTPA; the calculated safety factor (ratio of LD50 to effective dose) was 53 for Gd-DOTA and 28 for Gd-DTPA. The data suggest that in vitro stability correlates with in vivo safety.