Occurrence of breast cancer, renal cancer and multiple myeloma in a Nagasaki atomic bomb survivor

A 60-year-old female, who was exposed to the Nagasaki atomic bomb at 18 years old, had renal cancer and subsequently was found to have multiple myeloma (IgG kappa). She underwent the left mastectomy for breast cancer at 43 years old but was not given chemotherapy and radiotherapy. The karyotype of bone marrow cells was 46, XX. The estimated radiation dose was under 10 rads. While the effect of such a low-dose of radiation is considered to be almost negligible, there would be a possibility that in this case the risk of carcinogenesis was enhanced as her age advanced.     

Assessment of time-resolved, dynamic, contrast-enhanced MRDSA using radial sliding-window reconstruction.

Sliding-window reconstruction (SWR) has been recently introduced for rapid imaging that improves temporal resolution while maintaining signal-to-noise ratio (SNR) and spatial resolution. We assessed the quantity of 2-dimensional contrast-enhanced magnetic resonance digital subtraction angiography (2D CE-MRDSA) with non-Cartesian radial SWR in phantom and clinical studies. In phantoms, we compared the quantitative properties of time-intensity curves (TIC) obtained with dynamic 2D CE-MRDSA using SWR in a radial acquisition with those obtained by Cartesian acquisition. We calculated the mean variance and standard deviation among signal intensities in TICs and used SWR to study 2D CE-MRDSA in 5 patients with angiographically proven arteriovenous malformations. Using a 3-point grading scale, we individually scored vascular visualization capability and calculated time delay (TD) from the TIC in the feeding artery (FA), nidus, and draining vein (DV). The maximum signal intensity variance in Cartesian SWR was 6.58 +/- 2.27% among time-intensity curves and was 0.87 +/- 0.77% radial SWR. Signal intensity in radial SWR decreased significantly (P<0.001) compared with the Cartesian SWR. In clinical study, the mean rating on 2D CE-MRA of the feeding artery was 2.3, nidus, 2.6, and draining vein, 2.6. Mean delay time between DV and FA was 1.8 s. The radial SWR technique is useful for demonstrating the hemodynamic features of vascular malformations in the head with 2D CE-MRDSA.     

Lack of association between a polymorphism in the promoter region of the dopamine D2 receptor and personality traits.

Disturbances of the dopaminergic neurotransmitter system have been associated with a personality trait that involves novelty seeking. A functional polymorphism in the promoter region of the dopamine D2 receptor gene (DRD2) has been reported to be associated with schizophrenia. We examined the association between this polymorphism in the DRD2 promoter region and personality traits, as assessed with the Tridimensional Personality Questionnaire. No significant association emerged between the polymorphism in the DRD2 promoter region and personality traits. Entering sex and age as covariates in an analysis of covariance did not change the results. These data fail to confirm an association between a polymorphism in the promoter region of the DRD2 and personality traits.     

Effects of water immersion on mechanical properties of new esthetic orthodontic wire.

New fiber-reinforced plastic orthodontic wire (FRP wire) was fabricated with polymethyl methacrylate (PMMA) for the matrix and biocompatible CaO-P(2)O(5)-SiO(2)-Al(2)O(3) (CPSA) glass fibers for fibers that have not only high esthetics but also mechanical properties similar to those of metal wires. The purpose of this study was to evaluate the effects of water immersion on the mechanical properties of this new wire. The fiber-reinforced plastic orthodontic wire specimens were 0.5 mm in diameter with 29.1% to 60. 4% volume fraction of fibers that were 20 microm in diameter. A three-point flexural test was performed to obtain the elastic modulus and flexural load at the deflection of 1 mm under dry and wet conditions. Stress relaxation of the wires was tested under dry and wet conditions, and the wire diameters were measured before and at 20 days after immersion. The results showed that there were changes in the elastic modulus up until 10 days and in flexural load up until 20 days after immersion. The values of these two at 30 days after immersion were 93% and 87%, respectively, of those before immersion. Stress relaxation occurred rapidly from the start of immersion until about 60 minutes under dry conditions and about 120 minutes under wet conditions and then approached saturation. The swelling of hydrated fiber-reinforced plastic orthodontic wires affected the wire diameter, although this effect was not significant. The results of this study therefore suggest that the mechanical properties of fiber-reinforced plastic orthodontic wires are reduced by water immersion in the initial stage.     

MicroPET imaging of Cre-loxP-mediated conditional activation of a herpes simplex virus type 1 thymidine kinase reporter gene

Site-specific recombination tools such as the Cre-loxP system are used to create animal models where conditional gene deletion/activation studies are required. In the current proof of principle study, we have demonstrated that a PET reporter gene (PRG), the herpes simplex virus type 1 thymidine kinase (HSV1-tk), can be made to remain silent and can be activated by Cre-loxP-mediated recombination in cell culture and in living mice. An adenovirus carrying a silent HSV1-tk was tail-vein injected (1 x 10(9) PFU) in six transgenic mice that express Cre recombinase in their liver (Cre+) and in four control mice (Cre-). The liver-specific expression of the PRG in Cre+ mice was detected in the microPET following injection of the reporter probe, 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine ([(18)F]-FHBG). The [(18)F]-FHBG accumulation in the liver in terms of percent-injected dose per gram of tissue was 7.72+/-1.13 for the Cre+ mice and 0.10+/-0.02 for the Cre- mice (P<0.05) 48 h after adenoviral injection. These results were further validated by quantitative RT-PCR, western blotting and by in vitro assays for herpes simplex virus type 1 thymidine kinase enzyme activity. Thus by using the Cre-loxP system it is possible to modulate a PRG and noninvasively monitor the extent of Cre-loxP-mediated gene activation by imaging in a microPET scanner.     

Identification of the sites of asparagine-linked glycosylation on the human thyrotropin receptor and studies on their role in receptor function and expression

The amino-terminal ectodomain of human thyrotropin receptor (TSHR) contains six potential N-linked glycosylation sites (N-Xaa-S/T). This study was designed to evaluate the functional role of TSHR carbohydrates in detail. Because our previous mutagenesis study by Asn to Gln substitutions suggested the critical role of the first and third glycosylation sites (amino acids 77 and 113) for expression of the functional TSHR, we first constructed TSHR mutants having these two glycosylation sites to elucidate whether these two sites are sufficient for TSHR function and expression; this mutant however proved to be nonfunctional. Also the expression levels and function of TSHR mutants with a Ser/Thr to Ala substitution at the first or third glycosylation site were found to be intact. These data indicate that our previous data appear to result from amino acid substitution itself, not from disruption of glycosylation. The next series of the mutants was therefore constructed to identify at least how many glycosylation sites are necessary. Neither TSH binding nor cAMP response was detected in TSHR mutants with three glycosylation sites. However, the mutants with four glycosylation sites were fully functional in terms of TSH binding and cAMP production, although the expression levels were 30 to 40% of that in wild-type TSHR. Finally, Western blot revealed that all six glycosylation sites are actually glycosylated. These data indicate that 1) TSHR ectodomain contains six N-linked carbohydrates, and 2) glycosylation of at least four sites appears necessary for expression of the functional TSHR.     

The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim

Graves disease, a common organ-specific autoimmune disease affecting humans, differs from all other autoimmune diseases in being associated with target organ hyperfunction rather than organ damage. Clinical thyrotoxicosis is directly caused by autoantibodies that activate the thyrotropin receptor (TSHR). The etiology of Graves disease is multifactorial, with nongenetic factors playing an important role. Of the latter, there is the intriguing possibility that the molecular structure of the target antigen contributes to the development of thyroid-stimulatory autoantibodies (TSAb's). Among the glycoprotein hormone receptors, only the TSHR undergoes intramolecular cleavage into disulfide-linked subunits with consequent shedding of some of the extracellular, autoantibody-binding A subunits. Functional autoantibodies do not arise to the noncleaving glycoprotein hormone receptors. Recently, TSAb's were found to preferentially recognize shed, rather than attached, A subunits. Here we use a new adenovirus-mediated animal model of Graves disease to show that goiter and hyperthyroidism occur to a much greater extent when the adenovirus expresses the free A subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits. These data show that shed A subunits induce or amplify the immune response leading to hyperthyroidism and provide new insight into the etiology of Graves disease.