Tumor targeting by an aptamer.

Aptamers are small oligonucleotides that are selected to bind tightly and specifically to a target molecule. We sought to determine whether aptamers have potential for in vivo delivery of radioisotopes or cytotoxic agents. METHODS: TTA1, an aptamer to the extracellular matrix protein tenascin-C, was prepared in fluorescent and radiolabeled forms. After in vivo administration, uptake and tumor distribution of Rhodamine Red-X-labeled aptamer was studied by fluorescence microscopy. In glioblastoma (U251) and breast cancer (MDA-MB-435) tumor xenografts, biodistribution and imaging studies were performed using TTA1 radiolabeled with (99m)Tc. Tenascin-C levels and tumor uptake were studied in a variety of additional human tumor xenografts. To assess the effect of radiometal chelate on biodistribution, mercapto-acetyl diglycine (MAG(2)) was compared with diethylenetriaminepentaacetic acid and with MAG(2)-3,400-molecular-weight PEG (PEG(3,400)). RESULTS: Intravenous injection of fluorescent aptamer TTA1 produced bright perivascular fluorescence in a xenografted human tumor within 10 min. In the ensuing 3 h, fluorescence diffused throughout the tumor. Labeled with (99m)Tc, TTA1 displayed rapid blood clearance, a half-life of less than 2 min, and rapid tumor penetration: 6% injected dose (%ID)/g at 10 min. Tumor retention was durable, with 2.7 %ID/g at 60 min and a long-lived phase that stabilized at 1 %ID/g. Rapid tumor uptake and blood clearance yielded a tumor-to-blood ratio of 50 within 3 h. Both renal and hepatic clearance pathways were observed. Using the (99m)Tc-labeled aptamer, images of glioblastoma and breast tumors were obtained by planar scintigraphy. Aptamer uptake, seen in several different human tumors, required the presence of the target protein, human tenascin-C. Modification of the MAG(2) radiometal chelator dramatically altered the uptake and clearance patterns. CONCLUSION: TTA1 is taken up by a variety of solid tumors including breast, glioblastoma, lung, and colon. Rapid uptake by tumors and rapid clearance from the blood and other nontarget tissues enables clear tumor imaging. As synthetic molecules, aptamers are readily modified in a site-specific manner. A variety of aptamer conjugates accumulate in tumors, suggesting imaging and potentially therapeutic applications.     

Socioeconomic position and variations in coping strategies in musculoskeletal pain: a cross-sectional study of 1,287 40- and 50-year-old men and women.

OBJECTIVE: To examine the association between socioeconomic position and coping strategies in musculoskeletal pain. DESIGN AND SUBJECTS: Cross-sectional study of a random sample of 40- and 50-year-old Danes, participation rate 69%, n=7,125. The study included 1,287 persons who reported functional limitations due to musculoskeletal pain. METHODS: Data was collected by postal questionnaires and scales were developed on problem-solving coping and avoidant coping, based on a range of preliminary studies. Multivariate logistic regression analyses was used to study the correlation with socioeconomic position, measured by occupational social class. RESULTS: Among women, there was no correlation between social class and avoidant coping, but a significant decrease in the use of problem-solving coping by decreasing social class, adjusted odds ratio (OR) = 2.64 (95% confidence interval (CI) 1.31-5.32) in social class V vs social classes I + II. Among men, there was no correlation between social class and problem-solving coping, but a significant increase in the use of avoidant coping with decreasing social class, adjusted OR = 3.31 (95% CI 1.75-6.25) in V vs I + II. CONCLUSION: It is important for clinicians who advise and support patients in their response to musculoskeletal pain to be aware of socioeconomic differences in coping strategies. Gender differences in the association between socioeconomic factors and coping should be further investigated.     

Antisocial behavior of intravenous drug abusers: implications for diagnosis of antisocial personality disorder.

OBJECTIVE: A pattern of chronic adult antisocial behavior is not sufficient for the DSM-III-R diagnosis of antisocial personality disorder unless the early-onset criteria are satisfied, even if the adult criteria are met. The utility of the early-onset requirement for the diagnosis was examined in intravenous drug abusers, a population known to have high rates of irresponsible, aggressive, and criminal behavior. METHOD: The subjects were 237 drug abusers who had volunteered for an outpatient study of psychopathology and HIV risk behavior and infection. They completed a structured psychiatric interview as part of their participation in that study. The adult antisocial behavior of the group that met both the early-onset and the adult criteria for antisocial personality disorder, the group that met only the adult criteria, and the group that met neither the early-onset nor the adult criteria was then compared. RESULTS: Antisocial personality disorder (meeting the early-onset and adult criteria) was diagnosed in 44% of the sample; an additional 24% met only the adult criteria. The group with the diagnosis of antisocial personality disorder reported a more pervasive and more serious pattern of adult antisocial behavior than did the other groups, although antisocial behavior was commonplace in all three groups. CONCLUSIONS: Early onset of multiple antisocial behaviors identified a subset of drug abusers with important differences in the extent and severity of their adult antisocial behavior. The antisocial behavior of the group that met only the adult criteria suggests the possibility of a late-onset and less severe form of antisocial personality disorder.     

How much do 'attention' tests tell us?

Twelve measures commonly used to assess attentional processes were examined in a sample of 120 outpatients referred for neuropsychological evaluation. A single factor solution emerged. A second analysis partially replicated factors derived by Shum. McFarland, Bain, and Humphreys (1990). Classification rates (impaired vs. unimpaired) for the measures are presented. The implications of these findings for clinical assessment of attention are discussed     

Pharmacokinetics of isometronidazole. Basic model and estimation of the kinetic parameters from experimental data.

For the optimal timing of application of radiosensitizers in a course of radiotherapy it is important to know the sensitizer concentration at the time of irradiation. We have studied the pharmacokinetics of the hypoxic cell sensitizer isometronidazole in man and mouse and analyzed the data on the basis of an open two-compartment model after extravasal application. The parameter estimation is performed directly to avoid estimation biasing and data points from blood and tissue compartments are approximated simultaneously. The values obtained differ significantly from the estimations calculated by other authors for the same data.     

Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats.

The behavioural and biochemical effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, dizocilpine and memantine, and the competitive NMDA receptor antagonist, CGP 39551, were investigated in rats. Systemic injections of dizocilpine (0.33 mg/kg) increased locomotion and rearing in an open field, whereas memantine (20 mg/kg) increased only locomotor activity. CGP 39551 (10 and 20 mg/kg) did not change open field activity. Dopamine (DA) metabolism--as measured by the ratio of dihydroxyphenylacetic acid/dopamine (DOPAC/DA)--increased in response to dizocilpine in the prefrontal cortex and the nucleus accumbens. Memantine enhanced DOPAC/DA in the prefrontal cortex, the nucleus accumbens and to a lesser degree in the posterior striatum. In contrast to non-competitive NMDA receptor antagonists, CGP 39551 did not increase DA metabolism of subcortical structures and even decreased DOPAC/DA in the prefrontal cortex. These results indicate that competitive and non-competitive NMDA receptor antagonists affect spontaneous locomotion differentially in rats. The biochemical data imply that the stimulant actions non-competitive NMDA receptor antagonists are at least partially due to activation of ascending dopaminergic systems. Potential mechanisms involved in the differential effects of both types of NMDA receptor antagonists are discussed.     

Visualization of 3-D treatment plans with fast neutrons.

The treatment planning for radiotherapy with fast neutrons requires modifications of the planning systems used for photons. The neutron- and photon-component of the treatment fields must be determined and can then be used for separate calculations. The corrections for inhomogeneities are performed by use of attenuation coefficients and the corresponding corrections for changes in the kerma. The treatment planning system MEVAPLAN (Siemens) was modified to follow these requirements. Thus treatment planning for 14 MeV DT-neutrons could be performed. The multiplanar option is used to calculate 3D-dose distributions based on up to 40 serial CT slices. The generated three-dimensional dose matrix and the CT data are transferred via magnetic tape to the visualization system VOXEL-MAN developed at the University Hospital of Hamburg. This system uses a ray casting algorithm based on the generalized Voxel-model to display detailed 3D-images of human anatomy together with the calculated dose distribution. Different treatment plans for neutrons and photons are calculated and visualized. Various manipulations of the data-sets are displayed to improve the critical examination of the simulated dose distribution and to discern the quality of treatment techniques.     

Intra-articular injections and articular cartilage metabolism

Summary We studied the effects of repeated intra-articular injections of sterile 140 mM NaCl solution on articular cartilage in adult rabbits. After 20 injections into the knee joints over a period of 4 weeks, chondrocyte glucosaminoglycan synthesis was evenly reduced in all cartilage layers, accompanied by a significant proteoglycan depletion of the matrix which was most marked in the superficial half of the cartilage. These and other changes only partially reversed during a further 4-week period after the injections had been stopped. Our data underline the need for a clear-cut indication for intra-articular injections. The microtrauma caused by injection, in conjunction with the introduction of a carrier solution into the joint, may, at least when repeated at short intervals, lead to measurable damage to the articular cartilage.Recipient of grant no. Ne 308/1-1 from the Deutsche Forschungsgemeinschaft, Bonn, Germany     

Operational lumped constant for FDG in normal adult male rats.

We determined an operational value for the lumped constant to be used in measurements of the local rate of cerebral glucose use (lCMR(glc)) with FDG in normal adult male rats. METHODS: The standard quantitative autoradiographic method was used with 2-deoxy-d-(14)C-glucose ((14)C-DG) and with (14)C-FDG in awake normal adult male rats. Timed arterial blood samples were drawn for 45 min after the bolus and assayed for plasma glucose and (14)C concentrations. At the end of the 45-min experimental period, the rats were killed, and their brains were removed and divided in half sagittally. One hemisphere was immediately frozen and assayed for local (14)C concentrations by quantitative autoradiography; the other was weighed, homogenized in t-octylphenoxypolyethoxyethanol solution, and assayed for (14)C concentrations in the whole brain by liquid scintillation counting. Paired rats (3 pairs), one in each pair receiving (14)C-DG and the other receiving (14)C-FDG, were studied in parallel on the same day. Additional unpaired animals (n = 8) were studied with either (14)C-DG or (14)C-FDG but not in parallel on the same day. To calculate the lCMR(glc) in rats studied with (14)C-FDG, the rate constants for (14)C-FDG were estimated from the (14)C-DG values determined for rats and the (14)C-FDG/(14)C-DG ratios determined for humans. In all of the rats studied with either (14)C-DG or (14)C-FDG, the lCMR(glc) was first calculated in 12 representative brain structures with the lumped constant of 0.48 previously determined for (14)C-DG in rats. The ratio of the lCMR(glc) thus determined with (14)C-FDG to that determined with (14)C-DG for each structure was then multiplied by the lumped constant for (14)C-DG to estimate the lumped constant for (14)C-FDG. The lCMR(glc) and the lumped constant for FDG in the brain as a whole were similarly estimated from the tracer concentrations in the brain homogenates. RESULTS: The mean values for the lumped constant for FDG were found to be 0.71 and 0.70 in the autoradiographic assays and the assays with brain homogenates, respectively. CONCLUSION: The appropriate value for the lumped constant to be used in determinations of the lCMR(glc) in normal adult male rat studies with (18)F-FDG and small-animal PET scanners is 0.71.