Singularities explained: Response to Klein.

Klein [Klein, A. S. (2006). Separating transducer nonlinearities and multiplicative noise in contrast discrimination. Vision Research, 46, 4279-4293] questions the existence of intrinsic singularities in two-alternative force-choice (2AFC) Signal Detection Theory (SDT) models, suggesting that the singularities found in Katkov et al. [Katkov, M., Tsodyks, M., & Sagi, D. (2006a). Singularities in the inverse modeling of 2AFC contrast discrimination data. Vision Research, 46, 259-266; Katkov, M., Tsodyks, M., & Sagi, D. (2006b). Analysis of two-alternative force-choice Signal Detection Theory model. Journal of Mathematical Psychology, 50, 411-420] are due to discarding higher order terms in the Taylor expansion of d' and/or limited to steep psychometric functions. Here we provide some simple intuitive examples that illustrate the results described in Katkov et al. (2006a, 2006b). We show, for the constant noise model, that singularities exist when exact values of d' are computed and that the singularities are not limited to steep psychometric functions. In these cases the disambiguation of the different models requires millions of trials.     

Mechanism of uptake and retention of F-18 BMS-747 158-02 in cardiomyocytes: a novel PET myocardial imaging agent

Background BMS-747158-02 is a novel fluorine 18-labeled pyridazinone derivative designed for cardiac imaging. The uptake and retention mechanisms of F-18 BMS-747158-02 in cardiac myocytes were studied in vitro, and the biodistribution of F-18 BMS-747158-02 was studied in vivo in mice. Methods and Results Fluorine 19 BMS-747158-01 inhibited mitochondrial complex I (MC-I) in bovine heart submitochondrial particles with an IC₅₀ of 16.6±3 nmol/L that was comparable to the reference inhibitors of MC-1, rotenone, pyridaben, and deguelin (IC₅₀ of 18.2±6.7 nmol/L, 19.8±2.6 nmol/L, and 23.1±1.5 nmol/L, respectively). F-18 BMS-747158-02 had high uptake in monolayers of neonatal rat cardiomyocytes (10.3%±0.7% of incubated drug at 60 minutes) that was inhibited by 200 nmol/L of rotenone (91%±2%) and deguelin (89%±3%). In contrast, an inactive pyridaben analog, P-0 (IC₅₀ value>4 μmol/L in MC-1 assay), did not inhibit the binding of F-18 BMS-747158-02 in cardiomyocytes. Uptake and washout kinetics for F-18 BMS-747158-02 in rat cardiomyocytes indicated that the time to half-maximal (t_1/2) uptake was very rapid (approximately 35 seconds), and washout t_1/2 for efflux of F-18 BMS-747158-02 was greater than 120 minutes. In vivo biodistribution studies in mice showed that F-18 BMS-747158-02 had substatial myocardial uptake (9.5%±0.5% of injected dose per gram) at 60 minutes and heart-to-lung and heart-to-liver ratios of 14.1±2.5 and 8.3±0.5, respectively. Positron emission tomography imaging in the mouse allowed clear cardiac visualization and demonstrated sustained myocardial uptake through 55 minutes. Conclusions F-18 BMS-747158-02 is a novel positron emission tomography cardiac tracer targeting MC-I in cardiomyocytes with rapid uptake and slow washout. These characteristics allow fast and sustained accumulation in the heart.     

Role of Ca2+-independent phospholipase A2 and n-3 polyunsaturated fatty acid docosahexaenoic acid in prostanoid production in brain: perspectives for protection in neuroinflammation.

Various diseases of the central nervous system are characterized by induction of inflammatory events, which involve formation of prostaglandins. Production of prostaglandins is regulated by activity of phospholipases A(2) and cyclooxygenases. These enzymes release the prostaglandin precursor, the n-6 polyunsaturated fatty acid, arachidonic acid and oxidize it into prostaglandin H(2). Docosahexaenoic acid, which belongs to the n-3 class of polyunsaturated fatty acids, was shown to reduce production of prostaglandins after in vivo and in vitro administration. Nevertheless, the fact that in brain tissue cellular phospholipids naturally have a uniquely high content of docosahexaenoic acid was ignored so far in studies of prostaglandin formation in brain tissue. We consider the following possibilities: docosahexaenoic acid might attenuate production of prostaglandins by direct inhibition of cyclooxygenases. Such inhibition was found with the isolated enzyme. Another possibility, which has been already shown is reduction of expression of inducible cyclooxygenase-2. Additionally, we propose that docosahexaenoic acid could influence intracellular Ca(2+) signaling, which results in changes of activity of Ca(2+)-dependent phospholipase A(2), hence reducing the amount of arachidonic acid available for prostaglandin production. Astrocytes, the main type of glial cells in the brain control the release of arachidonic acid, docosahexaenoic acid and the formation of prostaglandins. Our recently obtained data revealed that the release of arachidonic and docosahexaenoic acids in astrocytes is controlled by different isoforms of phospholipase A(2), i.e. Ca(2+)-dependent phospholipase A(2) and Ca(2+)-independent phospholipase A(2), respectively. Moreover, the release of arachidonic and docosahexaenoic acids is differently regulated through Ca(2+)- and cAMP-dependent signal transduction pathways. Based on analysis of the current literature and our own data we put forward the hypothesis that Ca(2+)-independent phospholipase A(2) and docosahexaenoic acid are promising targets for treatment of inflammatory related disorders in brain. We suggest that Ca(2+)-independent phospholipase A(2) and docosahexaenoic acid might be crucially involved in brain-specific regulation of prostaglandins.     

Hutchinson's sign

Hutchinson's sign--pigmentation of the periungual tissues--is a valuable clue to the diagnosis of subungual melanoma. When present, this sign indicates malignant melanoma, however minimal the pigmentation or the histology may be. An illustrative case is presented.     

Plasma levels of antioxidant beta-carotene and alpha-tocopherol in uterine cervix dysplasias and cancer

Chronic human health problems, namely arteriosclerosis, myocardial ischemia, and cancer, may be caused by highly active oxygen species and may be preventable by antioxidant vitamins. In humans, the sources of two major antioxidants, beta-carotene and alpha-tocopherol, are dietary. In this study, we measured the plasma concentrations of beta-carotene and alpha-tocopherol by reverse-phase high-pressure liquid chromatography in a cross-sectional sampling of 116 women. Significantly reduced plasma levels of beta-carotene and alpha-tocopherol were observed in women with histopathologically diagnosed cervical dysplasias or cancer (p less than 0.0001 and p less than 0.005, respectively). There was an inverse association between the plasma levels of both beta-carotene and alpha-tocopherol and increasingly severe graded cervical histopathology. In groups with advanced dysplasias, the percentage of smokers was markedly increased and the women were comparatively older (p less than 0.0001). A strong association was noted between smoking status and plasma beta-carotene levels, independent of cervical pathology. However, this was not evident with respect to alpha-tocopherol. The findings suggest that the antioxidants beta-carotene and alpha-tocopherol have biologic functions that are interdependent in the pathogenesis of cervical intraepithelial lesions and cervical cancer.     

Malignant oncocytoma of the maxillary sinus— An ultrastructural study

A unique case of a malignant oncocytoma of the maxillary sinus is reviewed in detail. The ultrastructural findings are presented. The histologic and ultrastructural criteria that characterize onco-cytes and the clinicopathologic features of benign and malignant oncocytomas are discussed. This case represents the eleventh reported case that would truly qualify as a malignant oncocytoma of the paranasal sinuses.     

Hepatoprotective action of prostaglandin A2 analogs under CCl4-induced liver injury in vitro

Aim: The cytoprotective effects of six novel synthetic prostaglandin A(2) analogs against carbon tetrachloride (CCl(4)) as a toxic agent were studied with isolated rat liver hepatocytes in vitro. Results: It was found that hepatocytes treatment with CCl(4) induced: (i) a significant increase of lactic dehydrogenase (LDH) release from cytoplasm; (ii) leakage of glutamate dehydrogenase (GDH) and acid phosphatase from mitochondria and lysosomes, respectively; (iii) 10-fold increase of trien conjugates formation; and (iv) a reduction of free SH-groups by 50%. Prostanoids U-26, U-9 and U-34 decreased cytotoxic index of CCl(4) on average by 1.5-2.0 times and were more effective than PGI(2), the well-known hepatoprotector of prostanoids type. The protective action of the prostanoids was not a cAMP- or Ca(2+)-dependent process. However, prostanoids U-26, U-9 and U-34 normalized intracellular content of SH-groups, reduced trien conjugates formation by 60-80% and strongly prevented enzyme leakage through cellular membranes. They were also able to inhibit CCl(4) effects via decreasing cytochrome P(450)2E1 activity. Conclusion: The results obtained demonstrate that prostanoids provide cytoprotective effects on liver hepatocytes through the prevention of lipid peroxidation of the plasma and the cellular membranes and maintenance of their barrier function.     

Long-lasting changes in morphine-induced locomotor sensitization and tolerance in Long-Evans mother rats as a result of periodic postpartum separation from the litter: a novel model of increased vulnerability to drug abuse?

Daily postpartum separations from the litter produce enduring changes in anxiety and sensitivity to the antinociceptive effects of morphine in Long-Evans dams. We tested whether postpartum experience alters sensitivity to the effects of morphine on locomotor activity. Dams were tested 4-6 weeks after their pups were weaned, and had one of the following backgrounds: daily separation from the litter on postpartum days 2-14 for either 3 h (prolonged separation-LS) or 15 min (brief separation-BS), or no separation (nonhandled control-NH). After 2 consecutive days (B1-2) of baseline activity measurements, subjects were tested daily after s.c. injections of either morphine (10 mg/kg) or saline for 7 days and again on day 10. Beginning 5 days later, saline and 1.0-10 mg/kg of morphine were tested in all dams. On B1, LS and BS dams habituated slower than NH controls, yielding higher horizontal counts. LS dams failed to habituate across baseline days and were more active than other dams on B2. Sensitization, a progressive increase in horizontal activity, was more rapid and robust in LS and BS dams compared to NH animals. LS was the only group that developed tolerance to morphine-induced decreases in vertical activity. In LS dams with the history of morphine treatment, injection of saline resulted in higher horizontal activity and center time compared to saline-treated counterparts, indicative of conditioning. Among animals with a history of saline treatment, LS dams were more sensitive to morphine challenges than BS and NH dams. As a result of the robust and long-lasting increases in the ability of morphine to induce behavioral sensitization in litter-separated dams, periodic postpartum separation may represent a new animal model of increased vulnerability to substance abuse.     

MR Lymphography with a Lymphotropic T1-Type MR Contrast Agent: Gd-DTPA-PGM

A model system of a paramagnetic lymphotropic MR contrast agent (Gd-DTPA labeled polyglucose associated macrocomplex, PGM) for T¹-weighted MR imaging of lymph nodes in rats and rabbits was evaluated. Pharmacokinetic (tissue accumulation) and MR imaging data (optimal dose and timing parameters) were obtained in normal rats (n = 88) after subcutaneous (SC) injection of paramagnetic, radiolabeled [111In]Gd-DTPA-PGM. A rabbit model of lymph node metastases (n = 8) was ultimately used to demonstrate the potential of MR imaging with Gd-DTPA-PGM for nodal tumor detection. Maximum concentrations of Gd-DTPA-PGM were found in popliteal and paraaortic lymph nodes within 24 h after SC administration, and highest lymph node SNR values were obtained by MR imaging at this time point. The optimum imaging dose was 6–12 μmol Gd/kg. Tumor-lymph node contrast increased from 0.0 ± 1.2 precontrast to 19.2 ± 6.5 (spoiled gradient echo sequence, TR 50/TE 7/flip angle 60°) postcontrast and conspicuity of nodal metastases was improved. Gd-DTPA-PGM accumulates in lymph nodes after SC administration and significantly enhances lymph node signal intensity of normal animals but not metastatic lymph nodes.