Simultaneous occurrence of acute myelogenous leukemia and seminoma of the testis

Summary Simultaneous tumors are rarely encountered during the course of acute leukemias. We report on a case of seminoma of the testis that occurred during the evolution of acute myelogenous leukemia. To our knowledge, this stimultaneous association has not previously been described, but a causal relationship was not apparent in the present case. The likelihood of a common carcinogenesis existed, but direct exposure to carcinogens could not be established. Although the results of a physical examination and echography were normal at the time of diagnosis, we cannot exclude the presence of microscopic cancer of the testis. Since the dissemination pattern of seminoma is usually slower than that observed in this case and the disease remains limited to the lymph nodes for long periods following dissemination, the rapid development of the present case might have been attributable to the immunosuppression and the scrotal sepsis that occurred during the induction therapy. Immunosuppression might have stimulated the progression of a primary microscopic seminoma and the development of metastasis, whereas the scrotal sepsis and inflammation might have favored the occurrence of metastasis through bypass of the lymphatic barrier.     

Human urotensin-II potentiates the mitogenic effect of mildly oxidized low-density lipoprotein on vascular smooth muscle cells: comparison with other vasoactive agents and hydrogen peroxide.

Human urotensin-II (U-II) is the most potent vasoactive peptide identified to date, and may be involved in hypertension and atherosclerosis. We investigated the effects of the interactions between U-II or other vasoactive agents and mildly oxidized low-density lipoprotein (mox-LDL) or hydrogen peroxide (H2O2) on the induction of vascular smooth muscle cell (VSMC) proliferation. Growth-arrested rabbit VSMCs were incubated with vasoactive agents (U-II, endothelin-1, angiotensin-II, serotonin, or thromboxane-A2) in the presence or absence of mox-LDL or H2O2. [3H]Thymidine incorporation into DNA was measured as an index of VSMC proliferation. On interaction with mox-LDL or H2O2, U-II induced the greatest increase in [3H]thymidine incorporation among these vasoactive agents. A low concentration of U-II (10 nmol/l) enhanced the potential mitogenic effect of low concentrations of mox-LDL (120 to 337%) and H2O2 (177 to 226%). U-II at 50 nmol/l showed the maximal mitogenic effect (161%), which was abolished by G protein inactivator (GDP-beta-S), c-Src tyrosine kinase inhibitor (radicicol), protein kinase C (PKC) inhibitor (Ro31-8220), extracellular signal-regulated kinase (ERK) kinase inhibitor (PD98059), or Rho kinase inhibitor (Y27632). Mox-LDL at 5 microg/ml showed the maximal mitogenic effect (211%), which was inhibited by free radical scavenger (catalase), intracellular and extracellular antioxidants (N-acetylcysteine and probucol), nicotinamide adenine dinucleotide phosphate oxidase inhibitor (diphenylene iodonium), or c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results suggested that U-II acts in synergy with mox-LDL in inducing VSMC DNA synthesis at the highest rate among these vasoactive agents. Activation of the G protein/c-Src/PKC/ERK and Rho kinase pathways by U-II together with the redox-sensitive JNK pathway by mox-LDL may explain the synergistic interaction between these agents.     

Internalization of sst2, sst3, and sst5 receptors: effects of somatostatin agonists and antagonists.

The uptake of radiolabeled somatostatin analogs by tumor cells through receptor-mediated internalization is a critical process for the in vivo targeting of tumoral somatostatin receptors. In the present study, the somatostatin receptor internalization induced by a variety of somatostatin analogs was measured with new immunocytochemical methods that allow characterization of trafficking of the somatostatin receptor subtype 2 (sst2), somatostatin receptor subtype 3 (sst3), and somatostatin receptor subtype 5 (sst5) in vitro at the protein level. METHODS: Human embryonic kidney 293 (HEK293) cells expressing the sst2, sst3, or the sst5 were used in a morphologic immunocytochemical internalization assay using specific sst2, sst3 and sst5 antibodies to qualitatively and quantitatively determine the capability of somatostatin agonists or antagonists to induce somatostatin receptor internalization. In addition, the internalization properties of a selection of these agonists have been compared and quantified in sst2-expressing CHO-K1 cells using an ELISA. RESULTS: Agonists with a high sst2-binding affinity were able to induce sst2 internalization in the HEK293 and CHO-K1 cell lines. New sst2 agonists, such as Y-DOTA-TATE, Y-DOTA-NOC, Lu-DOTA-BOC-ATE (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; TATE is [Tyr3, Thr8]-octreotide; NOC is [1-NaI3]-octreotide; and BOC-ATE is [BzThi3, Thr8]-octreotide), iodinated sugar-containing octreotide analogs, or BIM-23244 were considerably more potent in internalizing sst2 than was DTPA-octreotide (where DTPA is diethylenetriaminepentaacetic acid). Similarly, compounds with high sst3 affinity such as KE108 were able to induce sst3 internalization. In sst2- or sst3-expressing cell lines, agonist-induced receptor internalization was efficiently abolished by sst2- or sst3-selective antagonists, respectively. Antagonists alone had no effect on sst2 or sst3 internalization. We also showed that somatostatin-28 and somatostatin-14 can induce sst5 internalization. Unexpectedly, however, potent sst5 agonists such as KE108, BIM-23244, and L-817,818 were not able to induce sst5 internalization under the same conditions. CONCLUSION: Using sensitive and reproducible immunocytochemical methods, the ability of various somatostatin analogs to induce sst2, sst3, and sst5 internalization has been qualitatively and quantitatively determined. Whereas all agonists triggered sst2 and sst3 internalization, sst5 internalization was induced by natural somatostatin peptides but not by synthetic high-affinity sst5 agonists. Such assays will be of considerable help for the future characterization of ligands foreseen for nuclear medicine applications.     

The ordered transmission disequilibrium test: detection of modifier genes

We consider the problem of detection of modifier genes that lead to variations in a disease‐related continuous variable (DRCV), such as the age of onset or a measure of disease severity, in a strategy of candidate genes. We propose a novel method, the ordered transmission disequilibrium test (OTDT), to test for a relation between the clinical heterogeneity expressed by a DRCV and marker genotypes of a candidate gene. The OTDT applies to trio families with one patients and his parents, all three genotyped at a bi‐allelic marker M. The OTDT aims to find a critical value of the DRCV which separates the sample of families in two subsamples in which the transmission rates are significantly different. We investigate the power of the method by simulations under various genetic models and covariate distributions and compare it with a linear regression analysis. Genet. Epidemiol. 2008. ©2008 Wiley‐Liss, Inc.     

Vasopressin receptors in the mouse (Mus musculus) brain: sex-related expression in the medial preoptic area and hypothalamus

We have investigated the distribution of vasopressin binding sites in the brain of male and female adult mice using a radio-iodinated ligand and film autoradiography. Vasopressin receptors were uncovered in various regions of the brain including the basal nucleus of Meynert, the substantia innominata, the hypothalamic paraventricular nucleus, the substantia nigra pars compacta and the hypoglossal nucleus. A sex-related difference in the expression of vasopressin receptors was seen in the medial preoptic area/anterior hypothalamus corresponding to the rat sexually dimorphic nucleus in the rat and in the hypothalamic mammillary nuclei. In both structures the autoradiographic labeling is more intense in females than in males. These observations confirm that vasopressin binding sites are present in the hypothalamic preoptic area of most species examined so far and that sex-related expression of neuropeptide receptors could trigger sex-related behavioral differences.     

Patch testing with beryllium alloy samples in guinea pigs

An experimental study was conducted in guinea pigs for the predictive assessment of the beryllium alloy hazard in occupational exposure of the skin to beryllium compounds. Guinea pigs were sensitized to beryllium sulfate according to the maximized Magnusson and Kligman test, and challenged with beryllium alloys and metallic copper, beryllium and aluminum samples. Results showed a delayed skin hypersensitivity reaction in 30 to 60% of pre-sensitized guinea pigs challenged with copper-beryllium alloys and aluminum-beryllium alloy. An inflammatory follicular reaction was induced by copper in both controls and pre-sensitized guinea pigs.     

Accuracy of planar reaching movements

This study examined the variability in movement end points in a task in which human subjects reached to targets in different locations on a horizontal surface. The primary purpose was to determine whether patterns in the variable errors would reveal the nature and origin of the coordinate system in which the movements were planned. Six subjects moved a hand-held cursor on a digitizing tablet. Target and cursor positions were displayed on a computer screen, and vision of the hand and arm was blocked. The screen cursor was blanked during movement to prevent visual corrections. The paths of the movements were straight and thus directions were largely specified at the onset of movement. The velocity profiles were bell-shaped, and peak velocities and accelerations were scaled to target distance, implying that movement extent was also programmed in advance of the movement. The spatial distributions of movement end points were elliptical in shape. The major axes of these ellipses were systematically oriented in the direction of hand movement with respect to its initial position. This was true for both fast and slow movements, as well as for pointing movements involving rotations of the wrist joint. Using principal components analysis to compute the axes of these ellipses, we found that the eccentricity of the elliptical dispersions was uniformly greater for small than for large movements: variability along the axis of movement, representing extent variability, increased markedly but nonlinearly with distance. Variability perpendicular to the direction of movement, which results from directional errors, was generally smaller than extent variability, but it increased in proportion to the extent of the movement. Therefore, directional variability, in angular terms, was constant and independent of distance. Because the patterns of variability were similar for both slow and fast movements, as well as for movements involving different joints, we conclude that they result largely from errors in the planning process. We also argue that they cannot be simply explained as consequences of the inertial properties of the limb. Rather they provide evidence for an organizing mechanism that moves the limb along a straight path. We further conclude that reaching movements are planned in a hand-centered coordinate system, with direction and extent of hand movement as the planned parameters. Since the factors which influence directional variability are independent of those that influence extent errors, we propose that these two variables can be separately specified by the brain.