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Biomedical subjects

M Lewin

Publications and source records attributed to M Lewin.

At least 19 recordsLinked to original sources

Kidney transplant function and histological clearance of virus following diagnosis of polyomavirus-associated nephropathy (PVAN).

Polyomavirus-associated nephropathy (PVAN) is managed by reduced immunosuppression with or without antiviral therapy. Data from 55 patients with biopsy-proven PVAN were analyzed for adverse outcomes and influence of baseline variables and interventions. During 20+/-11 months follow-up, the frequencies of graft loss, major and any functional decline were 15%, 24% and 38%, respectively. Repeat biopsies were performed in 45 patients with persistent PVAN in 47%. Low-dose cidofovir, IVIG and cyclosporine conversion were used in 55%, 20% and 55% of patients. No single intervention was associated with improved outcome. Of the variables examined, only degree of interstitial fibrosis at diagnosis was associated with kidney function decline. In contrast, donor source, interstitial fibrosis, proportion of BKV positive tubules and plasma viral load at diagnosis were all associated with failure of histological viral clearance. This retrospective, nonrandomized analysis suggests that: (i) Graft loss within 2 years of PVAN diagnosis is now uncommon, but ongoing functional decline and persistent infection occur frequently. (ii) Low-dose cidofovir, IVIG and conversion to cyclosporine do not abrogate adverse outcomes following diagnosis. (iii) Fibrosis at the time of diagnosis predicts subsequent functional decline. Further elucidation of the natural history of PVAN and its response to individual interventions will require prospective clinical trials.

Adult↗

[D-Dimer determination combined with clinical probability for the diagnosis of leg venous thrombosis].

OBJECTIVE: To evaluate the results of combination of D-Dimer test and simple clinical model for the diagnosis of deep vein thrombosis (DVT). MATERIALS AND METHODS: Inclusion: clinical suspicion of DVT. Non inclusion criteria were Clinical model performed by the referring physician included probability varying from high to low. D-Dimer test was performed by five different rapid techniques. Standard of reference was Doppler ultrasonography (DU) performed by a senior radiologist. RESULTS: Eight hundred and fifty-four DU were performed on a 14 months time period, including 206 suspicion of pulmonary embolism, 109 postoperative time period, 120 non-included or excluded patients, 278 incomplete observations, 141 complete observations. DVT was present in 33 cases and absent in the other 108 cases (prevalence 23%). Sensitivity and negative predictive value of the five tests were between 82 and 97% and 90 et 97%. The most sensitive test had a specificity of 36% and a positive predictive value of 32%. Combination of clinical model and D-Dimer test did not improve the diagnostic accuracy. CONCLUSION: None of the test evaluated in the present study, even when combined with the clinical model results, did allow the exclusion of DVT.

Formycins↗

Long-term follow-up after neoplastic seeding complicating percutaneous ethanol injection for treatment of hepatocellular carcinoma.

We describe a case of subcutaneous metastasis along the needle track after percutaneous ethanol injection (PEI) for treatment of hepatocellular carcinoma. After surgical resection and extrabeam radiation therapy the patient is alive without evidence of recurrence five years after PEI. One should pay attention to the abdominal wall around the needle track in interpreting CT or MR images of patients with previous PEI.

Abdominal Muscles↗

Structural and functional characterization of B-domain deleted recombinant factor VIII.

A new high-purity recombinant factor VIII preparation has been developed for the treatment of hemophilia A. Structurally, this factor VIII preparation, B-domain deleted recombinant factor VIII (BDDrFVIII), differs from other recombinant and plasma-derived factor VIII preparations in that most of the B-domain has been deleted. To ensure that BDDrFVIII contains the requisite structural and functional features, it has been subjected to detailed biochemical and biophysical characterization in comparison to the plasma-derived form of factor VIII. Laboratory studies have shown that the primary, secondary, and tertiary structures of BDDrFVIII and the posttranslational modifications are similar to those of the [80 + 90]-kd form of plasma-derived factor VIII. In addition, BDDrFVIII has full biologic activity compared with full-length factor VIII preparations.

Amino Acid Sequence↗

Hepatocyte targeting with Gd-EOB-DTPA: potential application for gene therapy.

RATIONALE AND OBJECTIVES: To evaluate the suitability of the liver-specific MRI contrast agent Gd-EOB-DTPA as a nonviral vector for gene therapy of hepatocellular carcinoma. METHODS: Specific uptake of Gd-EOB-DTPA was quantified by relaxometry in rat cultured hepatocytes and the hepatoma cells HepG2 and Huh7. Nonviral vectors for gene transfer were synthesized by coupling Gd-EOB-DTPA to polyethyleneimine or polylysine as DNA condensing agents, and their efficiency was studied using beta-galactosidase (lacZ) as the reporter gene. RESULTS: Gd-EOB-DTPA was specifically taken up by rat cultured hepatocytes (4.32 vs. 1.08 mmol/L in nonhepatocyte control cells) but not by the hepatoma cells; this uptake was concentration-dependently inhibited by Bromsulphtalein. Polycation linkages were achieved with yields of 0.9 Gd-EOB-DTPA molecule per polyethyleneimine molecule and 10 Gd-EOB-DTPA molecules per polylysine molecule. Incubating the cells with plasmids containing lacZ reporter gene and polyethyleneimine-Gd-EOB-DTPA resulted in a few blue (transfected) cells, whereas no blue cells were observed on incubation with polylysine-Gd-EOB-DTPA. CONCLUSIONS: Gd-EOB-DTPA is taken up by normal hepatocytes but not by HepG2 and Huh7 cells, probably because of the lack of the organic anion transporter in these hepatoma cells. The Gd-EOB-DTPA polycation conjugates, such as polyethyleneimine-Gd-EOB-DTPA, could serve as transfer vectors of interest for gene targeting imagery at the early stage of hepatocarcinogenesis. However, the transfer efficiency of such conjugates is low and requires improvement.

Animals↗

[Imaging mechanical complications of inferior vena cava filters].

Filter placement within the inferior vena cava is performed to prevent pulmonary embolism in patients with contraindications or failure of anticoagulant therapy. Several complications of vena cava filters have been described. However, mechanical complications related to IVC filters may not be of any clinical significance. The purpose of this pictorial essay is to present the imaging features of complications related to inferior vena cava filter placement.

Biomechanical Phenomena↗

Renovascular hypertension associated with neurofibromatosis: two cases and review of the literature.

The authors report two cases of renovascular hypertension associated with neurofibromatosis. A 19-year-old woman was admitted to our hospital with a complaint of abdominal pain and blood pressure of 180/120 mmHg. Examination revealed café-au-lait spots over her chest and extremities. Peripheral plasma renin activity (PRA) under basal conditions was 2.8 ng/ml/h and increased to 12.6 ng/ml/h after administration of 50 mg captopril. Plasma and urinary catecholamines were normal. Selective renal angiography showed left aneurysmal dilatation of the segmentary branch and right renal artery stenosis with multiple aneurysmal affecting different branches. Blood pressure was controlled by multiple drugs, including beta-blockers and angiotensin-converting enzyme inhibitor. Another patient, a 20-year-old woman, was admitted because of severe arterial hypertension, numerous café-au-lait spots, scoliosis, and mass over the right arm. PRA from the right renal vein was extremely elevated, and selective angiography demonstrated bilateral renal artery stenosis. Aortorenal bypass was performed successfully.

Adult↗

[Publication rate of original papers orally presented at the Journées Françaises de Radiologie 1996].

OBJECTIVE: The purpose of the present study was to determine the publication rate in Medline-indexed journals of papers originally presented at the Journées Françaises de Radiologie (JFR96). MATERIALS AND METHODS: Proceedings from the JFR 96 were reviewed by two observers in conference. A Medline search encompassing 1997-1999 was performed for the lead author of all abstracts of original papers. Publication year and the journal of publication were recorded. RESULTS: 456 oral presentations were analysed, 39 papers were subsequently published corresponding to a publication rate of 8.5%. 10 papers were published in Radiology, 4 in European Radiology and 4 in the Journal de Radiologie, the other 21 in other journals. Publication rate was significantly higher for two sessions: Research session (publication rate was 22%) and Bone and Joint session (publication rate was 16%). CONCLUSION: Less than 10% of abstracts presented at JFR 96 were subsequently published in Medline-indexed journals. This rate is lower than the publication rate of papers presented at other medical meetings.

Congresses as Topic↗

Evaluation of HSV-tk gene therapy in a rat model of chemically induced hepatocellular carcinoma by intratumoral and intrahepatic artery routes.

Transfer of the herpes simplex virus-thymidine kinase (HSV-tk) gene followed by the administration of ganciclovir (GCV) into hepatocellular carcinoma (HCC)-derived cell lines either in vitro or transplanted into nude mice has been shown to provide a potential strategy for HSV-tk-based gene therapy of HCC. We report herein an analysis of the antitumoral efficacy of two recombinant adenoviruses (Ads), Ad.CMVtk and Ad.AFPtk, in a relevant model of multifocal hepatic lesions induced in rats by a potent alkylating chemical carcinogen, diethylnitrosamine. Two routes of administration of the Ad were studied: intratumoral and intrahepatic artery injections. Both recombinant Ads, Ad.CMVtk and Ad.AFPtk, express the HSV-tk gene under the control of the early enhancer/promoter cytomegalovirus and alpha-fetoprotein regulatory gene sequences, respectively. The antitumor response was assessed by magnetic resonance imaging and by autopsy and histological analysis following postmortem. Tumor growth cessation was demonstrated by magnetic resonance imaging in large tumor nodules of size 5-8 mm treated by intratumoral administration of 2x10(9) pfu Ad.CMVtk plus i.p. treatment with GCV. We also show an antitumor efficacy in small tumor nodules of size <3 mm treated with 2x10(9) pfu Ad.CMVtk plus GCV by the intrahepatic artery route, albeit associated with an adverse toxicity. In vivo targeting of the HSV-tk gene to diethylnitrosamine-induced HCC cells with the recombinant Ad.AFPtk suppresses the hepatic toxicity in the nontumoral liver. The lower antitumor response would argue for the use of multiple injections of such adenoviral constructs. These observations may lead to potential approaches for designing gene therapy destined for early treatment of dysplastic nodules or advanced HCC in cirrhosis.

Adenoviridae↗

Imaging of tumour neovasculature by targeting the TGF-beta binding receptor endoglin.

In vivo imaging of endothelial markers in intact tumour neovasculature would have applications in assessing the efficacy of anti-angiogenic agents in clinical trials. Although a variety of different endothelial markers have been described, few have been evaluated as imaging markers. The transforming growth factor-beta (TGF-beta) binding receptor endoglin is a proliferation-associated endothelial marker. We hypothesised that endoglin would be an ideal target for imaging since it is strongly upregulated in proliferating endothelial cells of the tumour neovasculature. We used a radiolabelled monoclonal anti-endoglin antibody and compared its neovascular binding, accumulation and in vivo behaviour to an isotype-matched control IgG(2a). Our data show that the probe binds specifically and rapidly within minutes in vivo and that correlative autoradiography and immunohistology support the in vivo imaging findings. Imaging of abundantly expressed endothelial targets circumvents delivery barriers normally associated with other tumour targeting strategies, and can potentially be used to quantitate molecular angiogenic markers.

Antigens, CD↗

Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells.

The ability to track the distribution and differentiation of progenitor and stem cells by high-resolution in vivo imaging techniques would have significant clinical and research implications. We have developed a cell labeling approach using short HIV-Tat peptides to derivatize superparamagnetic nanoparticles. The particles are efficiently internalized into hematopoietic and neural progenitor cells in quantities up to 10-30 pg of superparamagnetic iron per cell. Iron incorporation did not affect cell viability, differentiation, or proliferation of CD34+ cells. Following intravenous injection into immunodeficient mice, 4% of magnetically CD34+ cells homed to bone marrow per gram of tissue, and single cells could be detected by magnetic resonance (MR) imaging in tissue samples. In addition, magnetically labeled cells that had homed to bone marrow could be recovered by magnetic separation columns. Localization and retrieval of cell populations in vivo enable detailed analysis of specific stem cell and organ interactions critical for advancing the therapeutic use of stem cells.

Animals↗

In vivo assessment of vascular endothelial growth factor-induced angiogenesis.

To determine whether vascular endothelial growth factor (VEGF)-induced tumor microvascularity is detectable by in vivo NMR imaging, an experimental study was conducted in nude mice. Human breast cancer cells (MCF-7) and MCF-7 cells stably transfected with the cDNA for the VEGF165 isoform (MV165) were grown in nude mice and models were characterized by RT-PCR, Western blotting, ELISA, immunohistochemistry and NMR imaging using a novel synthetic protected graft copolymer (PGC) as a vascular probe. MV165 tumors showed a 1.6-fold higher microvascular density by histology. Both tumors showed identical MR signal intensities on non-contrast and Gd-DTPA enhanced images. PGC enhanced MR imaging of tumoral vascular volume fraction (VVF), however, revealed significant differences between the 2 tumor types (MV165: 8.9 +/- 2.1; MCF-7: 1.7 +/- 0.5; p < 0.003), as expected from histology. VVF changes were more heterogeneous in the MV165 model both among tumors as well as within tumors as determined 3-dimensionally at submillimeter resolutions. Our results have potential applications for non-invasive assessment of angiogenesis by in vivo imaging and for clinical monitoring during angiogenic therapies.

Animals↗

Approaches and agents for imaging the vascular system.

Several classes of vascular imaging agents are described: (1) liposome-based blood cell mimetics; (2) plasma protein mimetics; (3) small molecules that bind to plasma proteins in the circulation. The characteristic features of the different agents are described and critically compared, including the advantages and potential pitfalls of each individual type.

Journal Article↗

Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB.

Targeted disruption of the mouse activin receptor type IIB gene (Acvr2b) results in abnormal left-right (LR) axis development among Acvr2b-/- homozygotes [Oh and Li, 1997: Genes Dev 11:1812-1826]. The resulting malformations include atrial and ventricular septal defects, right-sided morphology of the left atrium and left lung, and spleen hypoplasia. Based on these results, we hypothesized that mutations in the type IIB activin receptor gene are associated with some cases of LR axis malformations in humans. We report here characterization of the ACVR2B genomic structure, analysis of ACVR2B splice variants, and screening for ACVR2B mutations among 112 sporadic and 14 familial cases of LR axis malformations. Two missense substitutions have been identified, one of which appears in two unrelated individuals. Neither of these nucleotide changes has been found in 200 control chromosomes. We conclude that ACVR2B mutations are present only rarely among human LR axis malformation cases.

Activin Receptors, Type II↗

Cystogastric transmural drainage for the treatment of symptomatic cystic metastases from ovarian carcinoma.

Approximately 80% of ovarian cancers are discovered when they have already progressed to stage III or IV lesions. The prognosis is, therefore, poor despite intensive treatment. Intraperitoneal dissemination is one of the most frequent pathways of distant spread ovarian cancer and pseudocystic metastases usually occur. When such cystic metastases remain symptomatic despite antitumor treatment, viable options are limited because palliative surgery generates high operative morbidity and mortality. For many years, in patients in whom the risks associated with surgery are high, percutaneous drainage and sclerosis under radiologic guidance has been performed as an effective alternative option for various forms of abdominal fluid collection. Such a collection in pancreatic pseudocyst benefits from cystogastric transmural drainage to avoid external drainage and achieves the same results as surgical cystogastrostomy. We report this transmural drainage technique under image guidance used to drain a symptomatic cystic metastasis, which was compressing the stomach.

Ascitic Fluid↗

Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development.

Members of the transforming growth factor (TGF)-beta family of cell-signaling molecules have been implicated recently in mammalian left-right (LR) axis development, the process by which vertebrates lateralize unpaired organs (e.g., heart, stomach, and spleen). Two family members, Lefty1 and Lefty2, are expressed exclusively on the left side of the mouse embryo by 8.0 days post coitum. This asymmetry is lost or reversed in two murine models of abnormal LR-axis specification, inversus viscerum (iv) and inversion of embryonic turning (inv). Furthermore, mice homozygous for a Lefty1 null allele manifest LR malformations and misexpress Lefty2. We hypothesized that Lefty mutations may be associated with human LR-axis malformations. We now report characterization of two Lefty homologues, LEFTY A and LEFTY B, separated by approximately 50 kb on chromosome 1q42. Each comprises four exons spliced at identical positions. LEFTY A is identical to ebaf, a cDNA previously identified in a search for genes expressed in human endometrium. The deduced amino acid sequences of LEFTY A and LEFTY B are more similar to each other than to Lefty1 or Lefty2. Analysis of 126 human cases of LR-axis malformations showed one nonsense and one missense mutation in LEFTY A. Both mutations lie in the cysteine-knot region of the protein LEFTY A, and the phenotype of affected individuals is very similar to that typically seen in Lefty1-/- mice with LR-axis malformations.

Amino Acid Sequence↗

Hepatic nodules in Budd-Chiari syndrome: imaging features.

PURPOSE: To analyze the imaging features of nodules associated with Budd-Chiari syndrome. MATERIALS AND METHODS: The authors retrospectively studied images obtained in 23 patients with liver nodules who were being followed up for Budd-Chiari syndrome. Doppler ultrasonography was performed in all patients, computed tomography in 16, and magnetic resonance (MR) imaging in 20. The following lesion features were evaluated: location, number, size, vascularization, qualitative signal intensity at MR imaging, and homogeneity. Nodules were diagnosed on the basis of histopathologic findings or clinical and biologic data with no change at imaging during 2-year follow-up. RESULTS: All patients had histopathologic features of chronic Budd-Chiari syndrome. Four patients had hepatocellular carcinoma (HCC), with one to three lesions. The mean diameter of the largest HCC lesion in each patient was 7.3 cm. All HCC lesions were heterogeneous and had high signal intensity on T2-weighted MR images. Nineteen patients had multiple benign regenerative nodules, most of which were smaller than 4 cm. Most nodules were homogeneous and hyperintense on T1- and T2-weighted images. In 15 patients, nodules were hypervascular in the arterial phase. CONCLUSION: In patients with chronic Budd-Chiari syndrome, multiple (> 10) small (< 4-cm) lesions are suggestive of benignity.

Adult↗