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.     

Dexamethasone adjunctive treatment for tuberculous meningitis

During a 5-year period, 280 of 2010 patients admitted to the meningitis ward of a referral hospital in Cairo, Egypt, were clinically diagnosed as having tuberculous meningitis and were treated with either antituberculous chemotherapy and dexamethasone or antituberculous chemotherapy alone. Fatality rates and neurologic sequelae were compared for the 2 treatment groups in the 160 patients who had cerebrospinal fluid cultures positive for Mycobacterium tuberculosis. The overall mortality rate of 51% reflects the delay in receiving appropriate therapy (79% with symptoms for more than 2 weeks) and the severity of illness on admission (56% in coma, 39% drowsy). The fatality rate was significantly lower in the group receiving dexamethasone (43% vs. 59%, P less than 0.05), particularly in the drowsy patients (15% vs. 40% P less than 0.04), and in patients surviving long enough to receive at least 10 days of treatment (14% vs. 33%, P less than 0.02). Development of neurologic complications after initiation of therapy (4 vs. 10) and permanent sequelae (6 vs. 13) were significantly lower in the dexamethasone-treated group (P less than 0.02).     

Fusaric acid: a novel agent and mechanism to treat HNSCC.

OBJECTIVE: A new class of carboxylic acids has tumoricidal activity for head and neck squamous cell cancer (HNSCC). Fusaric acid (FA) can chelate divalent cations, especially zinc, and inactivate zinc finger proteins involved in DNA repair and protein synthesis. METHODS: 2 squamous carcinoma lines were utilized for in vitro and in vivo portions of this study. Cell counting and flow cytometry were used to analyze cells in culture in treatment and control groups over 96 hours. HNSCC subcutaneous implants were created in treatment and control groups of BALB-c nude mice (N = 30). RESULTS: In vitro studies demonstrated significant changes in cell numbers and cell cycle. In vivo studies of daily intralesional therapy for 1 month also showed reduced onset of growth and overall growth compared to controls. CONCLUSION: FA appears to have a tumoristatic/tumoricidal effect on HNSCC. Further nude mice studies are needed to optimize dosing and administration regimens for FA in anticipation of clinical trials.