Challenging level of rigid-body approach involving numerical elements (CHLORAINE) applied to repeated elastin peptides.

Elastic proteins and derived biomaterials contain numerous tandemly repeated peptides along their sequences, ranging from a few copies to hundreds. These repetitions are responsible for their biochemical, biological and biomechanical properties. These sequences are considered to be intrinsically disordered, and the variations in their behavior are actually mainly due to their high flexibility and lack of stable secondary structures originating from their unique amino acid sequences. Consequently, the simulation of elastic proteins and large elastomeric biomaterials using classical molecular dynamics is an important challenge. Here, we propose a novel approach that allows the application of the DURABIN protocol to repeated elastin-like peptides (r-ELPs) in a simple way. Four large r-ELPs were studied to evaluate our method, which was developed for simulating extracellular matrix proteins at the mesoscopic scale. After structure clustering applied on molecular dynamic trajectories of constitutive peptides (5-mers and 6-mers), the main conformations were used as starting points to define the corresponding primitives, further used as rigid body fragments in our program. Contributions derived from electrostatic and molecular hydrophobicity potentials were tested to evaluate their influence on the interactions during simple mesoscopic simulations. The CHLORAINE approach, despite the thinner granularity due to the size of the patterns used, was included in the DURABIN protocol and emerges as a promising way to simulate elastic macromolecular systems.

Elastin-derived peptides enhance melanoma growth in vivo by upregulating the activation of Mcol-A (MMP-1) collagenase.

BACKGROUND: Elastin peptides possess several biological activities and in vitro data suggest they could be involved in the early phase of melanoma growth. METHODS: Using diverse in vitro and in vivo techniques (cell proliferation, invasion and migration assays, zymography, western blots, collagen degradation assay, reverse transcription PCR, melanoma allographs and immunohistochemistry), we analysed the effect of elastin-derived peptides (EDPs) on B16F1 melanoma growth and invasion, as well as on the proteolytic systems involved. RESULTS: We found that EDPs dramatically promote in vivo tumour development of B16F1 melanoma, as well as their in vitro migration and invasion. The inhibition of serine proteases and matrix metalloproteinases (MMPs) activities, by aprotinin and galardin, respectively, demonstrated that these enzymes were involved in these processes. However, we found that EDPs did not increase urokinase-type plasminogen activator, tissue-type plasminogen activator or MMP-2 expression and/or activation, neither in vitro nor in vivo. Nevertheless, we observed a strong increase of pro-MMP-9 secretion in EDPs-treated tumours and, more importantly, an increase in the expression and activation of the murine counterpart of MMP-1, named murine collagenase-A (Mcol-A). Moreover, we show that plasminogen system inhibition decreases collagen degradation by this enzyme. Finally, the use of a specific blocking antibody against Mcol-A abolished EDP-induced B16F1 invasion in vitro, showing that this MMP was directly involved in this process. CONCLUSION: Our data show that in vivo, EDPs are involved in melanoma growth and invasion and reinforced the concept of elastin fragmentation as a predictive factor.

[Fibrous tissue(s): a key for lesion characterization in digestive diseases]. / Le(s) tissu(s) fibreux, clé(s) de la caractérisation lésionnelle en pathologie digestive.

Fibrosis is one of the hallmarks of inflammatory and repair processes in pathology. Various exogenous and endogenous stimuli, including tumor development, can induce inflammatory reactions. During the post-equilibrium phase after IV injection of non specific contrast media, CT and/or MR allow the study of these inflammatory answers to tumoral or infectious processes. Delayed enhancement of collagenic fibrous tissue during the late post-equilibrium phase is an essential complementary data in the characterization of many liver lesions: cirrhosis, cholangiocarcinoma, focal nodular hyperplasia, fibrous metastasis. but also for the differential diagnosis of pancreatic diseases (groove pancreatitis vs ductal adenocarcinoma) or of gastro-intestinal diseases (gastric adenocarcinoma vs lymphoma, mechanical complication vs inflammatory bouts of ileal Crohn's disease).

[Pneumobilia and MRCP: value of sagittal view]. / Aérobilie et cp-irm: intérêt des coupes sagittales.

Pneumobilia can lead to artifacts at MRCP obtained from thick coronal and coronal oblique slabs. Axial and sagittal images can both show gas bubbles in bile ducts but sagittal images depict more easily the presence of an air-fluid level.

[MRI of portal cavernoma with biliary involvement]. / IRM des cavernomes portaux à retentissement biliaire.

PURPOSE: To assess the value of MRI in the diagnosis of portal cavernoma with biliary obstruction. MATERIAL: and methods: six patients referred for clinical suspicion of biliary obstruction and portal cavernoma were explored with MRI. all patients were explored using a signa 1.5 t GE MR unit, with high gradient field strength and torso phased array coil. Biliary ducts were explored with ss-fse sequences of MR-cholangiopancreatography (MRCP), coronal and oblique coronal 20mm thick slices. Then, coronal T2w with shorter TE eff, MR-angiography and delayed T1w sequences were performed. CT scan and sonographic examinations of the liver were performed in all patients. Two patients were operated on and 2 underwent endoscopic retrograde cholangiography. RESULTS: Three different types of biliary involvement were found: in 3 cases findings that mimic cholangiocarcinoma spreading along the common bile duct and in 3 other cases multiple smooth extrinsic impressions along the common bile duct; in one patient MRCP demonstrated an irregular narrowing of the common bile duct mimicking chronic cholangitis. In all cases, the bile duct varices appeared of low T2W signal; in three cases, fibrosis was identified on delayed sequences. CONCLUSION: MRCP and MR-angiography can be proposed as a first imaging study in patients with portal cavernoma and cholestasis or bile duct dilatation.

[Effect of elastin peptides on the production of matrix metalloproteinase 2 by human skin fibroblasts in culture]. / Influence des peptides d'élastine sur la production de la métalloprotéinase matricielle-2 par les fibroblastes du derme humain en culture.

Soluble elastin-derived peptides from alkaline or elastase hydrolysis of insoluble elastin, as well as tropoelastin, increase matrix metalloproteinase-2 (MMP-2) production by human skin fibroblasts in culture as determined by gelatin zymography and ELISA. Such an effect is time and concentration dependent; it can be reproduced by synthetic elastin: VGVAPG, PGAIPG, and laminin: LGTIPG, hexapeptides and inhibited by lactose and is therefore elastin receptor-mediated. The steady state levels of MMP-2 mRNAs are invariant following elastin-fibroblasts interaction. Inhibition of phospholipase C (D-609), ADP-ribosylation factor (brefeldin), protein kinase C (RO-318220) and phospholipase D (1-propanol) totally abolished the elastin-mediated increase of MMP-2 production. It suggested that the post-transcriptional mechanism controlling the elastin-mediated overproduction of MMP-2 involved a cascade leading to phospholipase D activation.

[Diffuse pulmonary lymphangiomatosis in a young adult]. / Lymphangiomatose pulmonaire diffuse chez un adulte jeune.

We report a new case of diffuse pulmonary lymphangiomatosis in a 22 year-old man with a dysmorphic syndrome. The disease started with dyspnea which became rapidly disabling. The diagnosis was established from a pulmonary biopsy. Our patient developed severe chronic respiratory failure. Diffuse pulmonary lymphangiomatosis is a very uncommon disease. It is seen predominantly in children, exceptionally in adults, and affects both sexes equally. Symptoms like dyspnea and cough, pulmonary function with restrictive pattern, and interstitial syndrome, are not specific. Only pathology is evocative, characterized primarily by multifocal proliferation of pulmonary lymphatic vessels and increased number of complex anastomosing channels. These channels tend to dilate with time. The prognosis is poor and the treatment essentially palliative.

[Imaging of intraductal papillary mucinous tumor of the pancreas: literature review]. / Imagerie des tumeurs intracanalaires papillaires mucineuses du pancréas: revue de la littérature.

Intraductal papillary-mucinous tumor (IPMT) is defined as a syndrome consisting of dilatation of the main pancreatic duct and/or branch ducts associated with mucin overproduction. The purpose was to evaluate the usefulness of different imaging techniques (CT, EUS, ERCP) for determination of tumor invasion and pancreatic extension. Diagnosis often is delayed because it is confused with chronic pancreatitis or cystic neoplasms of the pancreas. It is difficult to rule out invasive malignancy. MRCP can be an essential imaging modality because it is a non-invasive technique. Intraductal ultrasound or pancreatoscopy could become in the future an additional useful preoperative procedure. A high frequency of invasive carcinoma in patients operated for pancreatic IPMT is observed. Surgical resection should be extended until a normal tissue margin is encountered.

[Imaging of the intrahepatic biliary tree with thick slice MR cholangiography]. / Imagerie des voies biliaires intrahépatiques en cholangiographie-IRM en coupes épaisses.

PURPOSE: To assess the value of single shot fast spin echo MR sequence (SS-FSE) in the evaluation of the normal and pathologic intrahepatic biliary tree. MATERIAL AND METHODS: 418 consecutive patients (457 examinations) referred for clinical and/or biological suspicion of biliary obstruction underwent MR cholangiopancreatography (MRCP). All patients were imaged with a Signa 1.5 T GE MR unit, with High Gradient Field Strength and Torso Phased Array Coil. Biliary ducts were imaged with SS-FSE sequence, coronal and oblique coronal 20 mm thick slices on a 256 x 256 matrix. Total acquisition time was 1 second. Source images were reviewed by two radiologists blinded to clinical information. In case of disagreement, a third radiologist's opinion was requested. In all cases, MRCP results were compared with direct biliary tract evaluation, other imaging studies and clinical and biological follow-up. RESULTS: In all cases, MRCP produced high quality images. Numerous branch of division were observed although the peripheral intrahepatic ducts were well seen in more than 90% in an area 2 cm below the capsule. The number of division was statistically higher when mechanical obstruction was present. Intrahepatic calculi or peripheral cholangiocarcinoma were well detect by MRCP. For the detection of cholangitis, MRCP sensitivity was 87.5% but the positive predictive value was only 57.7% because of a high number of false positive. The diagnosis of primary sclerosing cholangitis must be made only on strict criteria and slightly dilated peripheral bile ducts unconnected to the central ducts in several hepatic segments were a characteristic MR sign of primary sclerosing cholangitis. CONCLUSION: MRCP can be proposed as a first intention imaging technique for the evaluation of intrahepatic ducts.

[Incremental lower extremity CT venography, a simplified approach for the diagnosis of phlebitis in patients with pulmonary embolism]. / Phlébotomodensitométrie incrémentale des membres inférieurs, une approche simplifiée du diagnostic de la phlébite au cours des embolies pulmonaires.

PURPOSE: To demonstrate that incremental CT venography, performed at the time of CT pulmonary angiography, can easily diagnose deep venous thrombosis. Materials and Methods. Retrospective analysis of 152 combined incremental CT venography and CT pulmonary angiography. Results were compared to Doppler US examinations in 18 cases. RESULTS: 61% of venous thrombosis was found on incremental CT examination in case of pulmonary embolism. In 5 cases, isolated venous thrombosis was found without pulmonary embolism. The CT diagnosis of DVT was confirmed by US; CT appeared more accurate than US in the calf. CONCLUSION: CT venography combined with CT pulmonary angiography is a useful tool in order to obtain a comprehensive evaluation for thrombo-embolic disease.

Conformational dependence of collagenase (matrix metalloproteinase-1) up-regulation by elastin peptides in cultured fibroblasts.

We have established that treatment of cultured human skin fibroblasts with tropoelastin or with heterogenic peptides, obtained after organo-alkaline or leukocyte elastase hydrolysis of insoluble elastin, induces a high expression of pro-collagenase-1 (pro-matrix metalloproteinase-1 (pro-MMP-1)). The identical effect was achieved after stimulation with a VGVAPG synthetic peptide, reflecting the elastin-derived domain known to bind to the 67-kDa elastin-binding protein. This clearly indicated involvement of this receptor in the described phenomenon. This notion was further reinforced by the fact that elastin peptides-dependent MMP-1 up-regulation has not been demonstrated in cultures preincubated with 1 mm lactose, which causes shedding of the elastin-binding protein and with pertussis toxin, which blocks the elastin-binding protein-dependent signaling pathway involving G protein, phospholipase C, and protein kinase C. Moreover, we demonstrated that diverse peptides maintaining GXXPG sequences can also induce similar cellular effects as a "principal" VGVAPG ligand of the elastin receptor. Results of our biophysical studies suggest that this peculiar consensus sequence stabilizes a type VIII beta-turn in several similar, but not identical, peptides that maintain a sufficient conformation to be recognized by the elastin receptor. We have also established that GXXPG elastin-derived peptides, in addition to pro-MMP-1, cause up-regulation of pro-matrix metalloproteinase-3 (pro-stromelysin 1). Furthermore, we found that the presence of plasmin in the culture medium activated these MMP proenzymes, leading to a consequent degradation of collagen substrate. Our results may be, therefore, relevant to pathobiology of inflammation, in which elastin-derived peptides bearing the GXXPG conformation (created after leukocyte-dependent proteolysis) bind to the elastin receptor of local fibroblasts and trigger signals leading to expression and activation of MMP-1 and MMP-3, which in turn exacerbate local connective tissue damage.

The structures of elastins and their function.

Elastin structures and their significance towards elastic recoil properties have been reviewed. Starting from the initial hypothesis that elastin conformation is conditioned by that of its monomer, the structure of tropoelastin was first described using theoretical and experimental methods and a beta class folding type was evidenced for the isolated unbound tropoelastin molecules. The structure of elastin in the solid state was consistent with that of its monomer and consequently, fibrous elastin appeared constituted of globular tropoelastin molecules. Finally, theoretical and experimental considerations have led us to the conclusion that the functional form of the elastomer, water swollen elastin, could be a triphasic system comprising the protein chains, hydration water and solvent water. Following this description, the dynamic structural equilibria occurring within elastin hydrophobic domains and the plasticizing effect of water could explain elastin elasticity, in keeping with a classical entropic mechanism.

[Computed tomography study of the sigmoid colon: discriminating diagnostic criteria and interobserver correlations]. / Exploration tomodensitométrique du côlon sigmoïde: critères diagnostiques discriminants et corrélations interobservateurs.

PURPOSE: To assess the value of pericolonic findings at CT in the evaluation of the sigmoid colon. MATERIALS AND METHODS: A total of 210 CT examinations were retrospectively reviewed by 3 blinded radiologists. Data was analyzed to determine the interobserver correlation and the value of pericolonic and colonic wall findings in diagnosis of sigmoid colon pathology. RESULTS: The interobserver correlation for pericolonic findings was equal to or superior to that for colonic wall findings. The presence of abnormal pericolonic fat was the most sensitive (88%) and specific (93%) sign to differentiate a diseased sigmoid colon from a normal one or from sigmoid diverticulosis. Wall-thickening was less sensitive (82%) and specific (76%). Findings suggesting malignancy over diverticulitis included acute zone of transition, focal fatty infiltration, and lymph nodes. Symmetrical and circumferential wall thickening, target-like enhancement, and local fatty proliferation were findings suggesting colitis over diverticulitis. Wall thickening more than 15 mm, involvement of 15 cm or less, asymmetrical involvement, acute zone of transition, and homogeneous or heterogeneous enhancement were findings suggesting malignancy over colitis. CONCLUSION: To render a diagnosis, the evaluation of the fat infiltration must prevail on the parietal thickening appreciation.

Elastin: molecular description and function.

Elastin, the protein responsible for the elastic properties of vertebrate tissues, has been thought to be solely restricted to that role. As a consequence, elastin was conventionally described as an amorphous polymer. Recent results in the biomedical, biochemical and biophysical fields have lead to the conclusion that the presence of elastin in the extracellular space has very complex implications involving many other molecules. The present review describes the current state of knowledge concerning elastin as an elastic macromolecule. First, the genetic, biological, biochemical and biophysical processes leading to a functional polymer are described. Second, the elastic function of elastin is discussed. The controversy on elastin structure and elasticity is discussed and a novel dynamic mechanism of elasticity proposed. Finally, pathologies where the elastin molecule is involved are considered. This updated description of functional elastin provides the required background for the understanding of its pathologies and defines clearly the properties a substance should possess to be qualified as a good elastic biomaterial.

The secondary structure and architecture of human elastin.

The presented work constitutes the first structural characterization of both insoluble human elastin and its solubilized form, kappa-elastin. Structural data were reached following the use of Fourier transform infrared, near infrared Fourier transform Raman and circular dichroism optical spectroscopic methods and their quantitative analysis permitted us to estimate approximately 10% alpha-helices, approximately 35% beta-strands and approximately 55% undefined conformations in the global secondary structure of insoluble human elastin in the solid state. Following the use of the LINK method, the probable local distribution of the secondary-structure elements along the sequence was determined and compared to that obtained for bovine elastin, the historical standard of elastin. This comparison led us to propose a globular architecture for the human elastomer and permitted us to delineate some elements of its structure-elasticity relationship.