Differential kinase requirement for enhancement of Fc gamma R-mediated phagocytosis in alveolar macrophages by leukotriene B(4) vs. D(4)

In alveolar macrophages, leukotriene (IT) B(4) and cysteinyl LTs (LTC(4), LTD(4) and LTE(4)) both enhance Fc gamma receptor (Fc gamma R)-mediated phagocytosis. In the present study we investigated the role of specific PKC isoforms (PKC-alpha and -delta), the MAP kinases p38 and ERK 1/2, and PI3K in mediating the potentiation of Fc gamma R-mediated phagocytosis induced by addition of leukotrienes to the AMs. It was found that exogenously added LTB(4) and LTD(4) both enhanced PKC-delta and -alpha phosphorylation during Fc gamma R engagement. Studies with isoform-selective inhibitors indicated that exogenous LTB(4) effects were dependent on both PKC-alpha and -delta, while LTD(4) effects were exclusively due to PKC-delta activation. Although both exogenous LTB(4) and LTD(4) enhanced p38 and ERK 1/2 activation, LTB(4) required only ERK 1/2, while LTD(4) required only p38 activation. Activation by both LTs was dependent on PI3K activation. Effects of endogenous LTs on kinase activation were also investigated using selective LT receptor antagonists. Endogenous LTB(4) contributed to Fc gamma R-mediated activation of PKC-alpha, ERK 1/2 and PI3K, while endogenous cysLTs contributes to activation of PKC-delta, p38 and PI3K. Taken together, our data show that the capacities of LTB(4) and LTD(4) to enhance Fc gamma R-mediated phagocytosis reflect their differential activation of specific kinase programs. (C) 2008 Elsevier Ltd. All rights reserved.

On the unification of long-term survival models

In this paper we extend the long-term survival model proposed by Chen et al. [Chen, M.-H., Ibrahim, J.G., Sinha, D., 1999. A new Bayesian model for survival data with a surviving fraction. journal of the American Statistical Association 94, 909-919] via the generating function of a real sequence introduced by Feller [Feller, W., 1968. An Introduction to Probability Theory and its Applications, third ed., vol. 1, Wiley, New York]. A direct consequence of this new formulation is the unification of the long-term survival models proposed by Berkson and Gage [Berkson, J., Gage, R.P., 1952. Survival cure for cancer patients following treatment. journal of the American Statistical Association 47, 501-515] and Chen et al. (see citation above). Also, we show that the long-term survival function formulated in this paper satisfies the proportional hazards property if, and only if, the number of competing causes related to the occurrence of an event of interest follows a Poisson distribution. Furthermore, a more flexible model than the one proposed by Yin and Ibrahim [Yin, G., Ibrahim, J.G., 2005. Cure rate models: A unified approach. The Canadian journal of Statistics 33, 559-570] is introduced and, motivated by Feller`s results, a very useful competing index is defined. (c) 2008 Elsevier B.V. All rights reserved.

Intermolecular Contacts Influencing the Conformational and Geometric Features of the Pharmaceutically Preferred Mebendazole Polymorph C

Mebendazole (MBZ) is a common benzimidazole anthelmintic that exists in three different polymorphic forms, A, B, and C. Polymorph C is the pharmaceutically preferred form due to its adequated aqueous solubility. No single crystal structure determinations depicting the nature of the crystal packing and molecular conformation and geometry have been performed on this compound. The crystal structure of mebendazole form C is resolved for the first time. Mebendazole form C crystallizes in the triclinic centrosymmetric space group and this drug is practically planar, since the least-squares methyl benzimidazolylcarbamate plane is much fitted on the forming atoms. However, the benzoyl group is twisted by 31(1)degrees from the benzimidazole ring, likewise the torsional angle between the benzene and carbonyl moieties is 27(1)degrees. The formerly described bends and other interesting intramolecular geometry features were viewed as consequence of the intermolecular contacts occurring within mebendazole C structure. Among these features, a conjugation decreasing through the imine nitrogen atom of the benzimidazole core and a further resonance path crossing the carbamate one were described. At last, the X-ray powder diffractogram of a form C rich mebendazole mixture was overlaid to the calculated one with the mebendazole crystal structure. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2336-2344, 2009

Synthesis and characterization of a new mebendazole salt: Mebendazole hydrochloride

Mebendazole hydrochloride [(5-benzoyl-1H-benzimidazole-2-yl)-carbamic acid methyl ester hydrochloride, MBZ.HCl], a new stable salt of mebendazole (MBZ), has been synthesized and characterized. It can easily be obtained from recrystallization of forms A, B, or C of MBZ in diverse solvents with the addition of hydrochloric acid solution. Crystallographic data reveals that the particular conformation adopted by the carbamic group contributes to the stability of the network. The crystal packing is stabilized by the presence of three N-H...Cl intermolecular interactions that form chains along the b axis. The XRD analyses of the three crystalline habits found in the crystallization process (square-based pyramids, pseudohexagonal plates, and prismatic) show equivalent diffraction patterns. The vibrational behavior is consistent with crystal structure. The most important functional groups show shifts to lower or higher frequencies in relation to the MBZ polymorphs. The thermal study on MBZ center dot HCI indicates that the compound is stable up to 160 degrees C approximately. Decomposition occurs in four steps. In the first step the HCl group is eliminated, and after that the remaining MBZ polymorph A decomposes in three steps, as happens with polymorphs B and C. (C) 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:542-552, 2008.

A non-parametric vessel detection method for complex vascular structures

Modern medical imaging techniques enable the acquisition of in vivo high resolution images of the vascular system. Most common methods for the detection of vessels in these images, such as multiscale Hessian-based operators and matched filters, rely on the assumption that at each voxel there is a single cylinder. Such an assumption is clearly violated at the multitude of branching points that are easily observed in all, but the Most focused vascular image studies. In this paper, we propose a novel method for detecting vessels in medical images that relaxes this single cylinder assumption. We directly exploit local neighborhood intensities and extract characteristics of the local intensity profile (in a spherical polar coordinate system) which we term as the polar neighborhood intensity profile. We present a new method to capture the common properties shared by polar neighborhood intensity profiles for all the types of vascular points belonging to the vascular system. The new method enables us to detect vessels even near complex extreme points, including branching points. Our method demonstrates improved performance over standard methods on both 2D synthetic images and 3D animal and clinical vascular images, particularly close to vessel branching regions. (C) 2008 Elsevier B.V. All rights reserved.

Redox regulation of the mitochondrial K(ATP) channel in cardioprotection

The mitochondrial ATP-sensitive potassium channel (mK(ATP)) is important in the protective mechanism of ischemic preconditioning (IPC). The channel is reportedly sensitive to reactive oxygen and nitrogen species, and the aim of this study was to compare such species in parallel, to build a more comprehensive picture of mK(ATP) regulation. mK(ATP) activity was measured by both osmotic swelling and Tl(+) flux assays, in isolated rat heart mitochondria. An isolated adult rat cardiomyocyte model of ischemia-reperfusion (IR) injury was also used to determine the role of mK(ATP) in cardioprotection by nitroxyl. Key findings were as follows: (i) mK(ATP) was activated by O(2)(center dot-) and H(2)O(2) but not other peroxides. (ii) mK(ATP) was inhibited by NADPH. (iii) mK(ATP) was activated by S-nitrosothiols, nitroxyl, and nitrolinoleate. The latter two species also inhibited mitochondrial complex II. (iv) Nitroxyl protected cardiomyocytes against IR injury in an mK(ATP)-dependent manner. Overall, these results suggest that the mK(ATP) channel is activated by specific reactive oxygen and nitrogen species, and inhibited by NADPH. The redox modulation of mK(ATP) may be an underlying mechanism for its regulation in the context of IPC. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. (C) 2010 Elsevier B.V. All rights reserved.

Effects of Micelles and Vesicles on the Oximolysis of p-Nitrophenyl Diphenyl Phosphate: A Model System for Surfactant-Based Skin-defensive Formulations against Organophosphates

The rates of oximolysis of p-nitrophenyl diphenyl phosphate (PNPDPP) by Acetophenoxime; 10-phenyl-10-hydi-oxyiminodecanoic acid; 4-(9-carboxynonanyl)-1-(9-carboxy-1-hydroyiminononanyl) benzene; 1-dodecyl-2-[(hydroxyimino)methyl]-pyridinium chloride (IV) and N-methylpyridinium-2-aldoxime chloride were determined in micelles of N-hexadecyl-N,N,N-trimethylammonium chloride (CTAC), N-hexadecyl-N,N-dimethylammonium propanesulfonate and dioctadecyldimethylammonium chloride (DODAC) vesicles. The effects of CTAC micelles and DODAC vesicles on the rates of oxymolysis of O,O-Diethyl O-(4-nitrophenyl) phosphate (paraoxon) by oxime IV were also determined. Analysis of micellar and vesicular effects on oximolysis of PNPDPP, using pseudophase or pseudophase with explicit consideration of ion exchange models, required the determination of the aggregate`s effects on the pK(a), of oximes and on the rates of PNPDPP hydrolysis. All aggregates increased the rate of oximolysis of PNPDPP and the results were analyzed quantitatively. In particular, DODAC vesicles catalyzed the reaction and increased the rate of oximolysis of PNPDPP by IV several million fold at pH`s compatible with pharmaceutical formulations. The rate increase produced by DODAC vesicles on the rate of oximolysis paraoxon by IV demonstrates the pharmaceutical potential of this system, since the substrate is used as an agricultural defensive agent and the surfactant is extensively employed in cosmetic formulations. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1040-1052, 2009

Risk of recurrent stroke and death after first stroke in long-distance ski race participants

Background: Physical activity is of benefit for primary prevention of cardiovascular diseases, but it appears to increase the risk for atrial fibrillation. We aimed to study a cohort of patients following a first stroke in individuals with previous high physical activity, compare them to the general population with respect to recurrent stroke and death, and relate these to atrial fibrillation. Methods and results: From the participants of the Vasaloppet, the world's largest ski-race, and matched individuals from the general population (n=708 604), we identified 5964 patients hospitalized with a first-time stroke between 1994 and 2010. Individuals with severe diseases were excluded. One half percent of skiers and 1% of nonskiers were hospitalized due to stroke. The incidence rate was 8.3 per 100 person-years among skiers and 11.1 among nonskiers. The hazard ratio (HR) for recurrent stroke or death between the 2 groups was 0.76 (95% CI 0.67 to 0.86). The result was consistent in subgroups. The HR for death was 0.66 (95% CI 0.56 to 0.78) and for recurrent stroke 0.82 (95% CI 0.70 to 0.96). After adjustment for smoking and socioeconomic factors, the HR for death was consistent at 0.70 (95% CI 0.56 to 0.87) while the HR for recurrent stroke was not statistically significant. Outcomes for skiers with atrial fibrillation tended to show a lower risk than for nonskiers. Conclusions: This large cohort study supports the hypothesis that patients with a stroke and with prior regular physical activity have a lower risk of death, while their risk for recurrent stroke is similar to that of nonskiers. The skiers had a higher incidence of atrial fibrillation, but still no increased risk of recurring stroke.

Role of dietary fats in modulating cardiometabolic risk during moderate weight gain : a randomized double-blind overfeeding trial (LIPOGAIN study)

BACKGROUND: Whether the type of dietary fat could alter cardiometabolic responses to a hypercaloric diet is unknown. In addition, subclinical cardiometabolic consequences of moderate weight gain require further study. METHODS AND RESULTS: In a 7-week, double-blind, parallel-group, randomized controlled trial, 39 healthy, lean individuals (mean age of 27±4) consumed muffins (51% of energy [%E] from fat and 44%E refined carbohydrates) providing 750 kcal/day added to their habitual diets. All muffins had identical contents, except for type of fat; sunflower oil rich in polyunsaturated fatty acids (PUFA diet) or palm oil rich in saturated fatty acids (SFA diet). Despite comparable weight gain in the 2 groups, total: high-density lipoprotein (HDL) cholesterol, low-density lipoprotein:HDL cholesterol, and apolipoprotein B:AI ratios decreased during the PUFA versus the SFA diet (-0.37±0.59 versus +0.07±0.29, -0.31±0.49 versus +0.05±0.28, and -0.07±0.11 versus +0.01±0.07, P=0.003, P=0.007, and P=0.01 for between-group differences), whereas no significant differences were observed for other cardiometabolic risk markers. In the whole group (ie, independently of fat type), body weight increased (+2.2%, P<0.001) together with increased plasma proinsulin (+21%, P=0.007), insulin (+17%, P=0.003), proprotein convertase subtilisin/kexin type 9, (+9%, P=0.008) fibroblast growth factor-21 (+31%, P=0.04), endothelial markers vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin (+9, +5, and +10%, respectively, P<0.01 for all), whereas nonesterified fatty acids decreased (-28%, P=0.001). CONCLUSIONS: Excess energy from PUFA versus SFA reduces atherogenic lipoproteins. Modest weight gain in young individuals induces hyperproinsulinemia and increases biomarkers of endothelial dysfunction, effects that may be partly outweighed by the lipid-lowering effects of PUFA. CLINICAL TRIAL REGISTRATION URL: http://ClinicalTrials.gov. Unique identifier: NCT01427140.

The future of psychoanalytic institutes

The author contends that both conceptual and institutional problems permeate psychoanalytic institutes. Although institutional problems are historically based, they also derive from confusions around ill-defined concepts that lead to arbitrariness, authoritarianism, and the stifling of creativity. Psychoanalysis is a humanistic discipline that is touted as a science but is organized as a religion. Problems surrounding the right to train pervade psychoanalytic schisms, and transmission comes through processes of anointment. Institutional "false expertise" invokes the aura of anointment where training analysts pass down received truth through an esoteric pipeline depending on genealogy instead of function. Quasi-religious thinking and politics rush in to fill the gap between the level of claimed knowledge that affords qualification and the far lower level of real knowledge. Institutes should rely on evidence of candidates' performance and engage in open-ended inquiry