Gd-DTPA-cascade-polymer: Potential blood pool contrast agent for MR imaging

Gadolinium-DTPA (diethylenetriaminepentaacetic acid)-cascade-polymer, a potential new blood pool contrast agent for magnetic resonance (MR) imaging, was compared with a known blood pool agent, Gd-DTPA-polylysine, in an animal model. The relative signal intensities of liver, renal cortex, pancreas, and trunk muscle were assessed in 12 pigs between 4 seconds and 120 minutes after injection of a 20 μmol/kg dose of each contrast agent, by using a FLASH (fast low-angle shot) sequence. Except for muscle, all tissues showed visible enhancement after injection of either contrast agent. After injection of Gd-DTPA-polymer, enhancement patterns in the liver, renal cortex, and pancreas were similar to those seen after injection of Gd-DTPA-polylysine. No statistically significant differences in enhancement between the two contrast agents were found at any time point. The authors conclude that the contrast kinetics of Gd-DTPA-cascade-polymer are similar to those of Gd-DTPA-polylysine and that this agent may also be used as a blood pool contrast agent for MR imaging.     

Percutaneous transluminal rotational atherectomy in the treatment of peripheral vascular disease using a transluminal endatherectomy catheter (TEC): Initial results and angiographic follow-up

Purpose To evaluate the clinical results of percutaneous transluminal rotational atherectomy in the treatment of peripheral vascular disease. Methods Rotational atherectomy was performed in 39 patients aged 39–87 years (mean 66.6 years). A total of 71 lesions (43 stenoses and 28 occlusions) were treated in 40 limbs. Additional balloon angioplasty was required in 54% of lesions. Fifteen patients (37.5%) presented in Fontaine stage II, 10 patients (25%) in Fontaine stage III and 15 patients (37.5%) in Fontaine stage IV. Rotational atherectomy at 750 rpm was carried out over a 0.014-inch guidewire with continuous aspiration into a vacuum, bottle. Follow-up angiography and color flow Doppler examinations were performed in 22 patients (23 limbs) after a mean period of 6 months (range 2–14 months) Results There was one primary technical failure. In 36 of 40 lesions there was a good angiographic result with residual stenoses in less than 30%. In 70 lesions treated by rotational atherectomy, however, 54% showed residual stenoses of 30%–50% and these cases required additional balloon angioplasty. The mean ankle-brachial index improved significantly (p<0.001), from 0.49 before the procedure to 1.01 after the procedure. A single distal embolus, related to primary recanalization, occurred and there were two large inguinal hematomas. Cumulative clinical patency after 6 months was 83.8% and cumulative angiographic patency after 6 months was 79.1%. Conclusion Percutaneous rotational atherectomy is a promising approach for the treatment of chronic peripheral vascular disease. Further prospective, randomized studies are necessary to compare percutaneous transluminal angioplasty with this new technical approach.     

Cholinesterases and peanut agglutinin binding related to cell proliferation and axonal growth in embryonic chick limbs

Embryonic cholinesterases are assigned important functions during morphogenesis. Here we describe the expression of butyrylcholinesterase and acetylcholinesterase, and the binding of peanut agglutinin, and relate the results to mitotic activity in chick wing and leg buds from embryonic day 4 to embryonic day 9. During early stages, butyrylcholinesterase is elevated in cells under the apical ectodermal ridge and around invading motoraxons, while acetylcholinesterase is found in the chondrogenic core, on motoraxons and along the ectoderm. Peanut agglutinin binds to the apical ectodermal ridge and most prominently to the chondrogenic core. Measurements of thymidine incorporation and enzyme activities were consistent with our histological findings. Butyrylcholinesterase is concentrated near proliferative zones and periods, while acetylcholinesterase is associated with low proliferative activity. At late stages of limb development, acetylcholinesterase is concentrated in muscles and nonexistent within bones, while butyrylcholinesterase shows an inverse pattern. Thus, as in other systems, in limb formation butyrylcholinesterase is a transmitotic marker preceding differentiation, acetylcholinesterase is found on navigating axons, while peanut agglutinin appears in non-invaded regions. These data suggest roles for cholinesterases as positive regulators and peanut-agglutinin-binding proteins as negative regulators of neural differentiation.     

Structure-activity relationship of oxadiazoles and allylic structures in the Ames test: an industry screening approach

In recent years genotoxicity testing has become more and more important in the process of early screening for potential development compounds. In the case that a pharmacologically interesting structure is found to be positive in an in vitro mutagenicity test a straightforward approach starts by sorting out what substructure is responsible for the activity observed in the test. The Ames test is a rapid, convenient test system which has been effectively used in structure-activity relationship studies for mutagenicity, since it can rapidly establish differences in the mutagenic action of isomers and chemical analogs. The lead compound with a benzodiazepine-like structure and close analogs exhibited weak, but unequivocal positive effects in the Ames test (strains TA1535 and TA 100) after metabolic activation by rat liver homogenate fraction (S9). To identify substances within this class of compounds devoid of mutagenic liability an extensive structure-activity investigation was undertaken. More than 50 compounds were tested in the two critical bacterial strains, using a standard plate incorporation and a preincubation modification. It quickly became evident that the benzodiazepine structure was not involved. First hints that the allyl side chain were responsible for the Ames activity had to be refined in a more complex, but clear-cut structure-activity relationship during the course of the experiments. It was shown that all compounds with an allyl side chain, independent of the heterocycle, but surprisingly also all compounds with a specific arrangement of the heteroatoms in the oxadiazole ring, showed positive effects in at least one strain. Based on these investigations it was possible to select pharmacologically active structures without mutagenic liability.     

Immunohistochemical and molecular analysis of p53, RB,and PTEN in malignant peripheral nerve sheath tumors

The molecular basis of both sporadic and neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) is yet largely undetermined. Therefore, we analyzed a series of 12 MPNSTs - including two cases which arose in the setting of NF1 - for molecular alterations in the p53, retinoblastoma ( Rb), and PTEN tumor suppressor genes. Furthermore, the immunohistochemical expression of p53, RB, and PTEN protein was examined in these tumors. One mutation (8%), an A to T transversion leading to an amino acid exchange, was found in exon 5 of the p53 gene in a sporadic MPNST. In two other sporadic tumors (20%), loss of heterozygosity (LOH) of the p53 gene occurred. Nuclear overexpression of p53 protein was observed in ten tumors (83%). Loss of RB protein expression was seen in two MPNSTs (17%), and LOH of the Rb gene was detected in four tumors (44%), including the two NF1-associated MPNSTs, one of them showing concomitant loss of RB protein expression. No mutation in the PTEN gene was detected, and cytoplasmic immunoreactivity for the PTEN protein was maintained in eight MPNSTs (67%). We suggest that alterations in the p53 and RB pathway, both are essential in controlling the cell-cycle progression, are critical points in the tumorigenesis of sporadic and NF1-associated MPNSTs, whereas the PTEN gene seems to play no significant role in this process.     

Wasting during pregnancy increases the risk of mother-to-child HIV-1 transmission

OBJECTIVES: To examine whether wasting during pregnancy, as measured by weight loss and low weight gain, is associated with increased mother-to-child transmission (MTCT) of HIV-1. METHODS: This was a cohort study in Dar es Salaam, Tanzania, among 957 HIV-1-infected pregnant women. Weight was measured at the first prenatal visit and every month thereafter until delivery. Weight loss was defined as a weekly rate of weight gain 0 and /=167 g/wk, weight loss during pregnancy was related to higher risk of intrauterine MTCT (adjusted relative risk [RR] = 2.32, 95% CI = 1.23-4.36, P = 0.009), HIV positive at birth or fetal death (RR = 2.13, 95% CI = 1.40-3.24, P = 0.0004), and HIV positive at birth or early neonatal death (RR = 1.96, 95% CI = 1.26-3.07, P = 0.003). The rate of weight gain during the 3rd trimester was inversely related to the risk of intrapartum/early breast-feeding transmission (adjusted P value, test for trend = 0.05). CONCLUSIONS: Weight loss during pregnancy increases the risk of early MTCT. Identifying causes of wasting during pregnancy may provide clues for new strategies to prevent MTCT.     

A Log Ratio-Based Analysis of Individual Changes in the Composition of the Oral Microbiota in Different Dietary Phases

Background: Investigating the influence of nutrition on oral health has a long scientific history. Due to recent technical advances like sequencing techniques for the oral microbiota, this topic has gained scientific interest again. A basic challenge is to understand the influence of nutrition on the oral microbiota and on the interaction between the oral bacteria, which is also statistically challenging. Methods: Log-transformed ratios of two bacteria concentrations are introduced as the basic analytic tool. The framework is illustrated by application in an experimental study exposing eleven participants to different nutrition schemes in five consecutive phases. Results: The method could be sufficiently used to analyse the interrelation between the bacteria and to identify some bacterial groups with the same as well as different reactions to additional dietary components. It was found that the strongest changes in bacterial concentrations were achieved by the additional consumption of dairy products. Conclusion: A log ratio-based analysis offers insights into the relation of different bacteria while taking specific features of compositional data into account. The presented methods allow becoming independent of the behaviour of other bacteria, which is a disadvantage of common analysis methods of compositions. The results indicate that modulations of the oral biofilm microbiota due to nutrition change can be attained.