MR angiography of the spine

Postcontrast MR angiography complements the standard spinal MR imaging study by improving detection and display of normal and abnormal intradural vessels, primarily veins. Detection of abnormal veins facilitates diagnosis of spinal vascular malformations and vascular tumors. The most useful application has been in screening for spinal dural arteriovenous fistula, in which MR angiography demonstrates the medullary vein into which the fistula drains, thus allowing noninvasive identification of the spinal level of the fistula.     

Pin force measurement in a halo-vest orthosis, in vivo

Salmon calcitonin (sCT) is an example of one of the many bioactive peptides that require amidation of the carboxy terminus for full potency. We describe a method for the production of amidated sCT in the mammary gland of transgenic rabbits. Expression of a fusion protein comprising human alpha lactalbumin joined by an enterokinase cleavable linker to sCT was directed to the mammary gland under the control of the ovine beta lactoglobulin promoter. C-terminal amidation in vivo was achieved by extending the sCT by a single glycine residue that provides a substrate for endogenous amidating activity in the mammary gland. Full characterization of the released sCT demonstrated it to be equivalent to synthetic standard in terms of structure, purity, and potency.     

Reactivity of gemfibrozil 1-o-beta-acyl glucuronide. Pharmacokinetics of covalently bound gemfibrozil-protein adducts in rats

Acyl glucuronides are electrophilic metabolites that are readily hydrolyzed, undergo intramolecular rearrangement, and mediate the covalent binding of many acidic drugs to endogenous proteins. Gemfibrozil is extensively metabolized to gemfibrozil acyl glucuronide in humans and rats. The aims of this study were to demonstrate the reactivity of gemfibrozil glucuronide, determine whether gemfibrozil formed covalently bound protein adducts in vivo, describe the pharmacokinetics of adduct formation, and examine the role of gemfibrozil glucuronide in adduct formation. Rats were administered 150 mg/kg gemfibrozil daily for up to 37 days and killed 1, 2, 5, 10, 19, and 37 days after commencement of dosing, and 1, 2, 3, 8, 17, and 30 days after cessation of dosing. Plasma, liver, kidney, and heart were examined for adduct formation. Plasma was quantitatively the most important site for formation of gemfibrozil-protein adducts with mean (SE) steady-state concentrations of 31.40 (2.40) ng/mg protein attained by approximately the 10th day of dosing. Adduct half-life in plasma was 3.1 days, consistent with the elimination half-life of albumin. Mean (SE) kidney, liver, and heart steady-state adduct concentrations were 2.13 (0.11), 0.89 (0.35), and 0.95 (0.07) ng/mg protein, respectively. The rate of gemfibrozil-protein adduct accumulation seemed greatest in liver, but was similar in kidney and plasma, with approximately 2x, 16x, and 30x accumulation, respectively, over the dosing interval. In all tissues, adduct half-lives were significantly greater than those of the noncovalently bound gemfibrozil or gemfibrozil glucuronide.(ABSTRACT TRUNCATED AT 250 WORDS)     

A conundrum in molecular toxicology: molecular and biological changes during neoplastic transformation of human cells

The process of multistage carcinogenesis lends itself to the concept that the effects of carcinogens are mediated through dose-related, multi-hit, linear changes. Multiple in vitro model systems have been developed that are designed to examine the cellular changes associated with the progression of cells through the different stages in the process; however, these systems may have inherent limitations due to the cell lines used for these studies, the manner of assessing the effects of the carcinogens, and the subsequent growth and differentiation of the exposed cells. Each of these variables results in increasing levels of uncertainty relative to the correlation of the events with the actual process of human tumor development. Therefore, the prediction of the ultimate effect of any carcinogen is difficult. Moreover, relationships between individual biological endpoints resulting from carcinogen treatment appear at best to be approximations. The presence of an activated carcinogen inside the cell can give rise to multiple outcomes, only some of which may be critical events. For example, site-specific modification of the 12th and 13th codons of H-ras is different than that in the adjacent 14th and 15th codons. It is interesting to speculate what effect these differences might have on a biological outcome, e.g., transformation to anchorage-independent growth. The use of different model systems to examine the effects of activated carcinogens also creates additional problems. Comparisons of in vitro transformed cells with similar cells isolated from human tumors indicate that the culture environment appears to influence the expression of a particular phenotype, in that human tumor cells in culture express many of the same parameters as those found in cells transformed with carcinogens in vitro. If the process of transformation is linear, then less aggressive phenotypes should progress to a more aggressive transformed stage. However, in carcinogen-transformed human cells, the populations exhibit phenotypic diversity in that many of the transformed cells differentiate and fail to continue to divide in culture. Historically, we have assumed only a limited role for epigenetic modulation of molecular changes that occur during progression; however, our data suggest quite strongly that nonmalignant tumor populations can be converted to a more malignant phenotype without additional mutations taking place and, conversely, malignant populations can be downregulated to a nontumorigenic phenotype. Tumor cell plasticity is not only a fundamental characteristic of diverse types of human tumors, but also appears as an integral characteristic of carcinogen-transformed cells in vitro.     

Quantitative 13C NMR analysis of sequence distributions in poly(ethylene-co-1-hexene)

Different 13C NMR methods of determining triad distributions in two poly(ethylene-co-1-hexene) copolymers are examined using high signal-to-noise ratio 13C NMR spectra of the copolymers dissolved in deuterated 1,2,4-trichlorobenzene at 398 K. This examination includes a comparison of three integration techniques. The experimental impact of decoupler sidebands and significantly nonequal 13C NOE values are examined. A least-squares regression analysis technique for solving for triad mole fractions is tested and appears to be more reliable than two published algebraic expressions (and other expressions examined in the work reported here). The resultant triad mole fractions are compared to sequence distribution parameters expected by Bernoullian and first-order Markovian statistical models. On the basis of 13C NMR-determined average reactivity ratios, the copolymer designated sample B (5.3 mol % 1-hexene) appears to be a Bernoullian copolymer resulting from a single-site catalytic system. The copolymer designated sample S (3.6 mol % 1-hexene overall) is better described as a mixture of polyethylene and a Bernoullian copolymer with 6.4 mol % 1-hexene content, and thus appears to result from a multisite catalytic system.