Effects of three different doses of a bolus injection of gadodiamide: assessment of regional cerebral blood volume maps in a blinded reader study.

BACKGROUND AND PURPOSE: Reconstruction of first-pass bolus information to derive regional cerebral blood volume (rCBV) maps is commonly performed in many centers; however, various protocols with different doses of paramagnetic contrast injections have been reported. We evaluated the dose dependency of rCBV maps in a brain tumor population by using three different doses of gadodiamide injection to evaluate their diagnostic accuracy in blinded reader sessions. METHODS: Eighty-three patients with intraaxial brain tumors (72 gliomas) were studied at three centers and randomized to receive a bolus injection of 0.1, 0.2, or 0.3 mmol/kg per body weight of gadodiamide. rCBV maps were generated from T2*-weighted gradient-echo echoplanar sequences at 1.5 T. Data processing was performed according to the indicator dilution theory. RESULTS: The mean contrast-to-noise ratio (CNR) was significantly different between gadodiamide doses of 0.1 and 0.2 mmol/kg (CNR = 8.7 and 15.7) and between 0.1 and 0.3 mmol/kg (CNR = 17.7). No significant difference was found between doses of 0.2 and 0.3 mmol/kg. Sensitivity for the differentiation of benign and malignant brain tumors was 80%, 95%, and 91%, and specificity was 45%, 54%, and 43% by blinded readings at 0.1, 0.2, and 0.3 mmol/ kg, respectively, as compared with histologic findings. Nonblinded readings had a sensitivity of 83%, 100%, and 90% and a specificity of 82%, 100%, and 73% at 0.1, 0.2, and 0.3 mmol/kg, respectively. CONCLUSION: A dose of 0.2 mmol/kg of gadodiamide is recommended for reconstruction of rCBV maps if data are acquired with the T2*-weighted protocol described.

Thioxo amino acid pyrrolidides and thiazolidides: new inhibitors of proline specific peptidases.

Aminopeptidase P (APP), dipeptidyl peptidase II (DP II), dipeptidyl peptidase IV (DP IV) and prolyl oligopeptidase (POP) are proline specific peptidases. Hence, they are able to cleave peptide bonds containing the imino acid proline. Amino acid pyrrolidides (Pyrr) and thiazolidides (Thia) are well-known product analogue inhibitors of DP IV and POP. For the first time we describe the influence of a thioxo amide bond, incorporated into these compounds, on the inhibition of the proline specific peptidases. Taking into account the substrate specificity of these peptidases, we have synthesized Xaa-psi[CS-N]-Pyrr and Xaa-psi[CS-N]-Thia of the amino acids Ala, Phe, Val and Ile. The inhibition constants were determined for the above mentioned proline specific peptidases isolated from different sources. As a result, the serine proteases DP II, DP IV and POP were inhibited competitively, whereas metal-dependent APP displayed a linear mixed-type inhibition with inhibition constants up to 10(-4) M. Thioxylation of Xaa-Pyrr and Xaa-Thia led to a slight decrease of inhibition of DP IV and POP compared to Xaa-Pyrr and Xaa-Thia, though the inhibition constants were still in the range up to 10(-7) M. As Xaa-Thia exist as two isomers, we investigated isomer specific inhibition with regard to DP IV. Thus, our studies have revealed that DP IV was only inhibited by the Z isomer of the Xaa-psi[CS-N]-Thia. For the first time, Xaa-Pyrr and Xaa-Thia were characterized as inhibitors of DP II with inhibition constants in the micromolar range. In contrast to DP IV inhibition, the Xaa-psi[CS-N]-Pyrr and Xaa-psi[CS-N]-Thia have proven to be more potent inhibitors of DP II than the corresponding Xaa-Pyrr and Xaa-Thia. Thus, these Xaa-psi[CS-N]-Thia are new potent inhibitors especially suitable for DP II with K(i) values ranging in the upper nanomolar concentration.

Down-regulation of T cell activation following inhibition of dipeptidyl peptidase IV/CD26 by the N-terminal part of the thromboxane A2 receptor.

Using synthetic inhibitors, it has been shown that the ectopeptidase dipeptidyl peptidase IV (DP IV) (CD26) plays an important role in the activation and proliferation of T lymphocytes. The human immunodeficiency virus-1 Tat protein, as well as the N-terminal nonapeptide Tat(1-9) and other peptides containing the N-terminal sequence XXP, also inhibit DP IV and therefore T cell activation. Studying the effect of amino acid exchanges in the N-terminal three positions of the Tat(1-9) sequence, we found that tryptophan in position 2 strongly improves DP IV inhibition. NMR spectroscopy and molecular modeling show that the effect of Trp(2)-Tat(1-9) could not be explained by significant alterations in the backbone structure and suggest that tryptophan enters favorable interactions with DP IV. Data base searches revealed the thromboxane A2 receptor (TXA2-R) as a membrane protein extracellularly exposing N-terminal MWP. TXA2-R is expressed within the immune system on antigen-presenting cells, namely monocytes. The N-terminal nonapeptide of TXA2-R, TXA2-R(1-9), inhibits DP IV and DNA synthesis and IL-2 production of tetanus toxoid-stimulated peripheral blood mononuclear cells. Moreover, TXA2-R(1-9) induces the production of the immunosuppressive cytokine transforming growth factor-beta1. These data suggest that the N-terminal part of TXA2-R is an endogenous inhibitory ligand of DP IV and may modulate T cell activation via DP IV/CD26 inhibition.

Potent inhibitors of dipeptidyl peptidase IV and their mechanisms of inhibition.

Dipeptidyl peptidase IV (DP IV) is a proline specific serine protease which cleaves Xaa-Pro-dipeptides from the N-terminus of longer peptides. A series of product analogous amino acid amides containing different structure modifications like substitution of a ring atom, variation of the ring size and/or the introduction of a thioxo amide bond, phosphono amide bond or reduced amide bond were done to characterize these compounds as inhibitors of DP IV. These compounds are mostly classical reversible inhibitors of DP IV. In contrast amino acyl-2-cyanopyrrolidides inhibit DP IV according to a slow-binding mechanism with inhibition constants in the nanomolare range. On the other hand, diaryl dipeptide phosphonates inhibit irreversibly. In conclusion, this work shows, that the mechanism of inhibition of DP IV depends on the structure of the investigated compounds.

Critical evaluation of the specificity of MRI and TVUS for differentiation of malignant from benign adnexal lesions.

The aim of our work was to study the specificity of MRI in comparison with transvaginal US for differentiation of malignant from benign adnexal lesions. A total of 67 patients with clinically suspicious adnexal lesions were evaluated by MRI. Transaxial and coronal images were acquired using T1-weighted sequences before and following IV contrast and T2-weighted sequences. In all patients transvaginal ultrasound examinations (TVUS) were performed. For both imaging modalities each lesion was classified separately as either benign or malignant according to previously published criteria. Pathologic findings were available in 65 cases. Both MRI and TVUS correctly classified the 12 malignant lesions (sensitivity 100 %). Specificity (MRI: 78.2 %, TVUS: 65.5 %) and accuracy (MRI: 82 %, TVUS: 71.6 %) were higher with MRI than with TVUS, but differences were statistically not significant (p = 0.18 and p = 0.20, chi-square test). There was agreement/disagreement between findings of MRI and US in 52/15 lesions. The macroscopic criteria for malignancy are unspecific and result in a limitation of the specificity of both MRI and TVUS. The MRI technique is a valuable adjunct to TVUS by enabling further clarification of adnexal tumors with equivocal complex or solid vaginal sonographic findings.

Dynamic fast-gradient echo MR imaging of pancreatic tumours.

The purpose of this study was to determine the diagnostic utility of dynamic magnetic resonance imaging (MRI) of the pancreas. Twenty-eight adult patients with known or suspected pancreatic tumours were examined. Pre- and post-gadolinium (GdDTPA-BMA) scans were obtained in combination with an oral negative contrast medium (ferristene) to mark the gastrointestinal tract. In 6 cases a more precise diagnosis could be made by dynamic MRI compared to unenhanced MRI. Surgery could confirm the MR diagnosis based on contrast enhancement in 83% compared to 78% for CT. The results of signal intensity (SI) measurements show that a combination of differences in baseline values before enhancement and the slope of enhancement within the first 20 s is a reliable criterion to distinguish between normal pancreas and hypovascular tumours. These tumours already show lower SI values before as well as lower slopes after early enhancement. Mainly two effects facilitate the final MRI diagnosis: (1) the delineation of the pancreas from the duodenum by the negative contrast medium, and (2) the enhancement pattern of pancreatic tumours by gadolinium-enhanced dynamic MRI compared to normal tissue within the early enhancement after contrast injection.