Euphorigenic doses of cocaine reduce [123I]beta-CIT SPECT measures of dopamine transporter availability in human cocaine addicts

The in vivo potency of euphorigenic doses of intravenous cocaine for displacing [123I]beta-CIT ([123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binding to striatal dopamine transporters (DAT) was assessed in human cocaine addicts using single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n = 6) were injected with [123I]beta-CIT and imaged 24 h later under equilibrium conditions. Sequential cocaine infusions (0.28 +/- 0.03 and 0.56 +/- 0.07 mg/kg) produced significant (P < 0.0005) reductions in the specific to non-specific equilibrium partition coefficient, V3" (6 +/- 6 and 17 +/- 3%), a measure proportional to DAT binding potential. Regression analysis of the logit transformed data enabled reliable determination of the Hill coefficient (0.51) and 50% displacement (ED50) dose of cocaine (2.8 mg/kg). These preliminary data suggest that cocaine produces behavioral effects in humans at measurable levels of DAT occupancy.     

Modeling the interaction between propagating cardiac waves and monophasic and biphasic field stimuli: the importance of the induced spatial excitatory response

INTRODUCTION: Biphasic (BP) defibrillation waveforms have been shown to be significantly more efficacious than equivalent monophasic (MP) waveforms. However, when defibrillation fails, it tends to do so first in distal regions of the heart where induced field gradient magnitudes are lowest. We tested the hypothesis that the improved efficacy of BP waveforms results from their enhanced ability to prevent the initiation of new postshock activation fronts behind preexisting wavetails, rather than from any significantly improved ability to terminate preexisting wavefronts. METHODS AND RESULTS: An idealized computer model of a one-dimensional cardiac strand was used to investigate the spatial and temporal interactions between an underlying propagation front (or tail) and uniform MP or BP field stimuli of various intensities. Axial discontinuities from intercellular junctions induced sawtooth patterns of polarization during such field stimuli, enabling the shocks to interact directly with all cells. MP and BP diastolic thresholds were essentially equal. All suprathreshold MP and BP field stimuli successfully terminated preexisting wavefronts by directly depolarizing tissue ahead of those fronts, thus blocking their continued progression. However, the postshock response at the wavetail was significantly dependent on the shape and strength of the administered field. Low-strength MP stimuli induced an all-or-none excitation response across the wavetail, producing a sharp spatial transmembrane voltage gradient from which a new sustained anterogradely propagating wavefront was initiated. In contrast, low-strength BP field stimuli induced a spatially graded excitatory response whose voltage gradient was insufficient to initiate such a wavefront. Higher-strength MP and BP stimuli both produced graded excitatory responses with no subsequent propagation. CONCLUSIONS: Shock-induced spatial "all-or-none" excitatory responses facilitate, and graded excitatory responses prevent, the postshock initiation of new propagating wavefronts. Moreover, BP field stimuli can induce such graded excitatory responses at significantly lower stimulus strengths than otherwise equivalent MP stimuli. Therefore, these results support an alternative "graded excitatory response" mechanism for the improved efficacy of BP over MP field stimuli in low gradient regions.     

A robotic system for percutaneous renal access

PURPOSE: Percutaneous renal access can be challenging, particularly when the collecting system is not distended. Precise entry into a selected calyx facilitates subsequent percutaneous manipulations, but this skill requires extensive experience. In an attempt to improve accuracy while decreasing technical challenges, we developed a robotic system that automates the task of fluoroscopic image-guided percutaneous needle placement. MATERIALS AND METHODS: The prototype system consisted of a three degree-of-freedom robot with a needle injector end-effector. Imaging was provided by a biplanar fluoroscope. After correction of image distortion and fluoroscope calibration, robot to image-space registration was completed. To validate the system's ability to insert a needle into a calyx, ex vivo porcine kidneys suspended in agarose gel and distended with iodinated contrast solution were used as a model. In situ renal access tests with three 20 kg. pigs were performed. Access was confirmed by passing a flexible wire or aspirating iodinated contrast from the collecting system. RESULTS: The diameter of target calyces ranged from 3 to 7 mm. The in vitro accuracy of final needle tip positioning was 0.43 mm. In the ex vivo model, successful "one stick" access occurred on 10 of 12 attempts (83%). In situ access on the first attempt was successful for 6 of 12 target calyces (50%). Needle or tissue deflection accounted for each failure. CONCLUSION: The feasibility of a robotic system to assist in the percutaneous access of small and delicate renal calyces has been demonstrated. Additional work in reducing procedural steps and correcting for tissue deflection during needle passage is necessary to improve accuracy and to allow for clinical application.     

Apparent mtDNA heteroplasmy in Alzheimer's disease patients and in normals due to PCR amplification of nucleus-embedded mtDNA pseudogenes

In an unprecedented finding, Davis et al. [Davis, R. E., Miller, S., Herrnstadt, C., Ghosh, S. S., Fahy, E., Shinobu, L. A., Galasko, D., Thal, L. J., Beal, M. F., Howell, N. & Parker, W. D., Jr. (1997) Proc. Natl. Acad. Sci. USA 94, 4526-4531] used an unusual DNA isolation method to show that healthy adults harbor a specific population of mutated mitochondrial cytochrome c oxidase (COX) genes that coexist with normal mtDNAs. They reported that this heteroplasmic population was present at a level of 10-15% in the blood of normal individuals and at a significantly higher level (20-30%) in patients with sporadic Alzheimer's disease. We provide compelling evidence that the DNA isolation method employed resulted in the coamplification of authentic mtDNA-encoded COX genes together with highly similar COX-like sequences embedded in nuclear DNA ("mtDNA pseudogenes"). We conclude that the observed heteroplasmy is an artifact.     

Changes in bone tissue of women under condition of 120 days antiorthostatic hypokinesia

A comparative analysis was carried out between the hair content of basic trace metals in patients with atherosclerosis, ischemic heart disease (IHD) and findings from their immunogrammes. Close correlation was found out between changes in concentrations of Mn, Cu, Fe, Si, Zn, Ca and processes of activation of basic leucocyte populations characteristic of IHD course and alterations in humoral immune response peculiar to the above patients. Conclusions were reached about presence of the aforementioned changes in the pathogenesis of atherosclerosis, IHD.     

Ovine brain natriuretic peptide in cardiac tissues and plasma: effects of cardiac hypertrophy and heart failure on tissue concentration and molecular forms

It is well established that lymphoid dendritic cells (DC) play an important role in the immune system. Beside their role as potent inducers of primary T cell responses, DC seem to play a crucial part as major histocompatibility complex (MHC) class II+ "interdigitating cells" in the thymus during thymocyte development. Thymic DC have been implicated in tolerance induction and also by some authors in inducing major histocompatibility complex restriction of thymocytes. Most of our knowledge about thymic DC was obtained using highly invasive and manipulatory experimental protocols such as thymus reaggregation cultures, suspension cultures, thymus grafting, and bone marrow reconstitution experiments. The DC used in those studies had to go through extensive isolation procedures or were cultured with recombinant growth factors. Since the functions of DC after these in vitro manipulations have been reported to be not identical to those of DC in vivo, we intended to establish a system that would allow us to investigate DC function avoiding artificial interferences due to handling. Here we present a transgenic mouse model in which we targeted gene expression specifically to DC. Using the CD 11c promoter we expressed MHC class II I-E molecules specifically on DC of all tissues, but not on other cell types. We report that I-E expression on thymic DC is sufficient to negatively select I-E reactive CD4+ T cells, and to a less complete extent, CD8+ T cells. In contrast, it only DC expressed I-E in a class II-deficient background, positive selection of CD4+ T cells could not be observed. Thus negative, but not positive, selection events can be induced by DC in vivo.     

Regression of experimental brain tumors with 6-thioxanthine and Escherichia coli gpt gene therapy

The identification of transgenes with antitumor activity is critical to the development of gene therapy of cancer. Retrovirus-mediated transfer of the Escherichia coli gpt gene into rat C6 glioma cells without subsequent selection still inhibited the proliferation of this mixed polyclonal population upon addition of the prodrug, 6-thioxanthine, with an ID50 of 4.1 microM, whereas parental C6 cells were not affected at a concentration of 500 microM. In a time-course assay, effects of the prodrug on the mixed polyclonal cell proliferation required at least 10 days of exposure. In mixed co-cultures, a bystander effect was not present over the first 4 days of prodrug exposure, but required trypsinization of the co-cultures and replating at lower densities. This "modified" bystander assay thus revealed a 50% decrease in C6 cell proliferation, even when the initial ratio of gpt-expressing to parental C6 cells was as low as 1:19. In a nude mouse model of subcutaneous tumors, co-grafts of C6 glioma and gpt-retrovirus producer cells displayed retarded growth upon exposure to 6-thioxanthine (6-TX). In a nude mouse model of intracerebral tumors, grafting of the gpt-retrovirus producer cells leads to an 80% reduction in intracerebral tumor volumes after 6-TX treatment. This reduction results in a 28% increase in the mean time of survival of animals that harbor intracerebral tumors (p < 0.0005). These antitumor effects indicate that the gpt/6-TX enzyme/prodrug pair is a promising alternative to the thymidine kinase gene and ganciclovir combination in the gene therapy of cancer.     

To sell or not to sell: Exploring sellers' trust and risk of chargeback fraud in cross‐border electronic commerce

Over the past few decades, chargeback fraud from buyers has been identified as a major risk faced by online sellers, particularly small‐ and medium‐sized enterprises, in cross‐border electronic commerce. However, most previous studies have focused on trust and perceived risk from the buyers' perspective and in domestic online marketplaces, while neglecting the importance of sellers' trust and perceived risk in the success of online transactions and the significance of cross‐border transactions. To fill this gap in the literature, this study examines both the antecedents and the impacts of sellers' trust in buyers and their perceived risk of chargeback fraud on sellers' intention to trade with buyers in the context of cross‐border e‐commerce. To this end, we develop a conceptual model that identifies a set of institutional mechanisms to enhance sellers' trust and reduce their perceived risk. Hypotheses are tested via a survey of 443 sellers on DHgate.com , one of the major cross‐border e‐commerce websites connecting the small‐ and medium‐sized enterprises of mainland China with overseas buyers. Our research makes concrete contributions to e‐commerce research and generates useful insights for third‐party online transaction platforms and online trade policy makers.