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Background RBx 14255 is a fluoroketolide in pre-clinical evaluation with potent activity against MDR Gram-positive pathogens. Objectives To investigate the efficacy of RBx 14255 against bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis or Haemophilus influenzae in an experimental murine meningitis model. Methods In vitro activity of RBx 14255 was evaluated against clinical isolates of S. pneumoniae, N. meningitidis and H. influenzae. The in vivo efficacy of RBx 14255 was evaluated against bacterial meningitis, induced with S. pneumoniae 3579 erm(B), S. pneumoniae MA 80 erm(B), N. meningitidis 1852 and H. influenzae B1414 in a murine meningitis model. Results RBx 14255 showed strong in vitro bactericidal potential against S. pneumoniae, N. meningitidis and H. influenzae with MIC ranges of 0.004-0.1, 0.03-0.5 and 1-4 mg/L, respectively. In a murine meningitis model, a 50 mg/kg dose of RBx 14255, q12h, resulted in significant reduction of bacterial counts in the brain compared with the pretreatment control. The concentration of RBx 14255 in brain tissue correlated well with the efficacy in this mouse model. Conclusions RBx 14255 showed superior bactericidal activity in time-kill assays in vitro and in vivo in an experimental murine meningitis model. RBx 14255 could be a promising candidate for future drug development against bacterial meningitis.

[Image: see text] The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORγt inverse agonist. Structure–activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.

Introduction: Out-of-hospital cardiac arrest (OHCA) remains a highly morbid public health problem. Despite improving practices and clear guidelines, mortality from this condition remains high at 90%, with survivors often suffering from poor neurologic outcomes. To determine the feasibility of quality improvement collaboratives to narrow gaps between evidence-based practice and patient care for OHCA, we conducted a pilot study of the AHA Resuscitation Collaborative. Methods: Eight emergency medical service agencies participated in the quality improvement collaborative pilot project. We identified several OHCA performance measures to assess the quality of care, guide collaborative activities, and monitor change in performance over time. Over the course of four learning sessions, participants were trained in quality improvement and performance measurement, analyzed performance measure results, and shared successes and challenges. Results: Five remaining agencies underwent the process outlined in Figure 1. Adherence to performance measures, including compression rate compliance (Figure 2), improved over the course of the collaborative. Compression rate compliance in Figure 2 corresponds to the process improvement efforts of the Chesapeake Fire Department with achievement of goals for optimal range of chest compression rate between 100 and 120 compressions per minute during resuscitations. Conclusion: As demonstrated in Virginia, the collaborative approach was an effective framework to improve OHCA care. Improvement in performance measures, the evident commitment of dedicated peers and colleagues, consistent collaboration, and the effective diffusion of best practices all support the continued use of this model.

We present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for its in vitro and in vivo activities against sensitive and macrolide-resistant Streptococcus pneumoniae . RBx 14255 showed excellent in vitro activity against macrolide-resistant S. pneumoniae , including an in-house-generated telithromycin-resistant strain ( S. pneumoniae 3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistant S. pneumoniae 3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. The in vivo efficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation of S. pneumoniae ATCC 6303 and systemic infection with S. pneumoniae 3390 NDDR strains. The 50% effective dose (ED 50 ) of RBx 14255 against S. pneumoniae ATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistant S. pneumoniae 3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.

Revisiting, from a Marxist perspective, the World Bank's discourse on Social Funds, we highlight three findings. One, Social Funds gets deployed in the context of a larger Third Worldist discourse of poverty management, which in turn helps deepen the logic of capitalist development. Two, generating a class-focused understanding of Social Funds (via the concept of social surplus), we argue that class processes and need processes constitute one another and through this conduit emerges a relation between global capital and the poverty alleviation programme of Social Funds. Lastly, interrogating the management approach underlying Social Funds leads us to question claims of decentralisation and participation. Our analysis exposes an underlying process of subjectification by way of a control mechanism exercised through the code of conduct encapsulated in that managerial approach. Copyright , Oxford University Press.

The MIC 90 of RBx 14255, a novel ketolide, against Clostridium difficile was 4 μg/ml (MIC range, 0.125 to 8 μg/ml), and this drug was found to be more potent than comparator drugs. An in vitro time-kill kinetics study of RBx 14255 showed time-dependent bacterial killing for C. difficile . Furthermore, in the hamster model of C. difficile infection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate for C. difficile treatment.

Using a class focused Marxist approach, we elucidate the adopted position of Indian small-scale sector as a devalued other within the adopted development paradigm that accords primacy to Capital and West. In the background of this understanding of small-scale sector, we demonstrate how the New Economic Policy in the era of globalization could be theorized as a tool to obtain the (post) colonial hegemony of capital over the small-scale sector. Copyright The Author 2008. Published by Oxford University Press on behalf of the Cambridge Political Economy Society. All rights reserved., Oxford University Press.

In mainstream approaches, children’s labour is either to be banned or is not recognised. As a result, their association with the process of wealth creation and its distribution is occulted. In this paper, taking a classfocused Marxian approach, we question and critique the premise of this supposition on children's working world. As against the received rendition of children's working world, we offer an alternative method of locating and analysing the relation of children with the process of wealth creation and its distribution. Rehabilitating the children as an economic actor in the class-focused terrain opens up new avenues to ask and offer questions including policy-related ones that have hitherto been put aside from the discussion on children's working world.

Women with systemic lupus erythematosus (SLE) are at risk for premature atherothrombosis independent of Framingham risk factors. We investigated whether endothelial cell (EC) apoptosis predicts abnormal vasomotor tone and contributes to circulating tissue factor (TF) levels in this disease. Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation were determined in women with SLE, healthy control subjects, and subjects with coronary artery disease (CAD) (n = 43/group). Quantification of circulating apoptotic ECs was performed by flow cytometry (CD146+ cells that stained for Annexin V [CD146AnnV+]) and immunofluorescent microscopy. Plasma TF was measured by enzyme-linked immunosorbent assay (ELISA). Compared with healthy control and CAD subjects, patients with SLE had higher numbers of circulating CD146AnnV+ cells (10 ± 3, 18 ± 5, and 89 ± 32 cells/mL, respectively, mean ± SEM; P < .01). Increased CD146AnnV+ cells correlated strongly with abnormal vascular function (P = .037). After adjusting for known predictors of endothelial function, CD146AnnV+ was the only variable that predicted FMD (β = –4.5, P < .001). Increased CD146AnnV+ was strongly associated with elevated levels of circulating TF (r = .46, P = .002). Circulating apoptotic ECs are elevated in young women with SLE and strongly correlate with markedly abnormal vascular function and elevated TF levels. Heightened endothelial apoptosis may represent an important mechanism for development of atherothrombosis in SLE.

The products of nitric oxide synthase (NOS) and angiotensin-converting enzyme (ACE) play a critical role in determining vessel wall structure and function. Polymorphisms in both genes have been independently demonstrated to influence propensity to cardiovascular events. The purpose of this study was to determine the influence of the homozygous G849T(Glu298 Asp) polymorphism in NOS III on peripheral conduit artery endothelial function and to elucidate the modifier role, if any, of a common ACE polymorphism. Three hundred and ninety-seven consecutive subjects presenting to the cardiac catheterization laboratory of the University of Michigan over a period of 18 months were recruited. DNA was extracted and polymerase chain reaction (PCR) analysis for ACE and NOS polymorphisms performed. Patients with homozygosity for G849T at both loci (TT) who belong to DD and II ACE genotype (groups 1 and 2) and those who are negative for this polymorphism (GG) and belong to either DD or II genotype (groups 3 and 4) were identified. The four groups then underwent determination of conduit endothelial function. Heterozygosity of Glu298-Asp or the ID variant of the ACE were not studied. Median FMD value in the TT-DD group was 0.20 (-3.17, 2.01) compared with 2.23% (-0.29, 4.17) in the GG-II group. Median values in the TT-II and the GG-DD groups were 3.04 (-1.16, 6.61) and 2.46% (-1.83, 6.52) respectively. These values were not statistically significant (p > 0.05 by one-way ANOVA). Median nitroglycerin-mediated dilation in the four groups did not differ between the four groups (p = NS by ANOVA). Atherosclerosis burdens as assessed by angiography were not different across the groups. In conclusion, the homozygous NOS III variant (GG) status does not seem to interact additively with the ACE homozygous DD genotype in determining flow-mediated vasodilation in individuals with established atherosclerosis and pre-existent endothelial dysfunction.

This paper makes two related contributions. First, the dual economic structure underlying development is shown as producing a distinct conception of other comprising of a devalued third world which is foregrounded and world of the third which is excluded. This dyad of inclusion-exclusion of other is produced in relation to the centers of capitalism and modernism. The category of third world helps to displace the language-experience-logic-ethos of the other a la world of the third such that development works over and transforms world of the third, but via the trope of a devalued third world. We then use this framework to explore the relation of global capitalism with world of the third in the Indian context, a relation that is shown to be two fold. There is on one hand an attempt to dismantle world of the third as part of the development trope of overcoming the third world. On the other, through inclusive development, an attempt is made to directly intervene in the economy of world of the third so as to address the problems of income inequality and social exclusion, again under the trope of uplifting the devalued third world.

This paper makes two related contributions. First, the dual economic structure underlying development is shown as producing a distinct conception of other comprising of a devalued third world which is foregrounded and world of the third which is excluded. This dyad of inclusion-exclusion of other is produced in relation to the centers of capitalism and modernism. The category of third world helps to displace the language-experience-logic-ethos of the other a la world of the third such that development works over and transforms world of the third, but via the trope of a devalued third world. We then use this framework to explore the relation of global capitalism with world of the third in the Indian context, a relation that is shown to be two fold. There is on one hand an attempt to dismantle world of the third as part of the development trope of overcoming the third world. On the other, through inclusive development, an attempt is made to directly intervene in the economy of world of the third so as to address the problems of income inequality and social exclusion, again under the trope of uplifting the devalued third world.

Adriamycin (ADR) is a commonly used chemotherapeutic agent that is believed to exert its effects through the generation of oxygen free radicals. We hypothesized that administration of a single dose of ADR results in endothelial nitric oxide synthase (eNOS)-dependent generation of superoxide (O2·-) and acute endothelial dysfunction. A single dose of ADR (10 mg/kg i.v.) administered to rabbits resulted in rapid attenuation of agonist-dependent responses to acetylcholine and calcium ionophore (A23187). In vitro exposure of ring segments to ADR for 2·- generation measured by electron spin resonance (ESR) with the spin trap segments 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO) that was abolished by endothelial denudation and incubation with diphenyliodonium (DPI) (10 mM) but not L-NMMA (10 mM). Brachial artery flow-mediated dilation (FMD) in patients undergoing chemotherapy with ADR was markedly attenuated after a single dose of ADR (6.5 6 1.0 to 2.5 6 1.1% (p = 0.0004, time to end of infusion 27 6 8 min) while endothelial-independent dilatation with nitroglycerin was unchanged (16.3 6 3.1 and 14.33 6 2.1% respectively, p = 0.36). Serum nitrite and nitrate concentrations fell from 50 6 6 mmol/l pre-ADR to 33 6 6 mmol/l post-ADR infusion (p = 0.0005) while serum concentrations of CD141 thrombomodulin and von Wille-brand factor (vWF) activity remained unchanged after ADR infusion (36 6 13 to 52 6 22% ng/ml versus 3.25 6 0.98 to 3.01 6 0.91%, respectively, p = NS for pre versus post for both). Doppler indices of diastolic function (IVRT, DT and E/A ratios) were not altered in response to ADR. In conclusion, ADR administration results in rapid depletion of systemic NO· levels and attenuation of agonist-dependent responses in rabbits and flow-mediated dilation in the brachial artery of humans. ESR measurements in rabbit ring suggest an endothelial origin for radical production via flavin-containing oxido-reductases such as eNOS or NADPH cytochrome P450 reductase. These fi ndings may have implications for cardiovascular complications noted with ADR.

Objective To compare microvascular and macrovascular functions in a cohort of patients with primary and secondary Raynaud's phenomenon (RP) who were matched for demographic, risk factor, and severity profiles. Methods Forty patients with primary or secondary RP matched for vascular risk factors and severity scores underwent testing of endothelial function and cold pressor responsiveness of the brachial artery. Microvascular perfusion of the digital vasculature was assessed using laser Doppler fluxmetry in response to reactive hyperemia. Plasma was assayed for endothelin 1 (ET-1), asymmetric dimethylarginine (ADMA), intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemoattractant protein 1 (MCP-1). Results Patients with RP had abnormal vasoconstrictor responses to cold pressor tests (CPT) that were similar in primary and secondary RP. There were no differences in median flow-mediated and nitroglycerin-mediated dilation or CPT of the brachial artery in the 2 populations. Patients with secondary RP were characterized by abnormalities in microvascular responses to reactive hyperemia, with a reduction in area under the curve adjusted for baseline perfusion, but not in time to peak response or peak perfusion ratio. Plasma ET-1, ADMA, VCAM-1, and MCP-1 levels were significantly elevated in secondary RP compared with primary RP. There was a significant negative correlation between ET-1 and ADMA values and measures of microvascular perfusion but not macrovascular endothelial function. Conclusion Secondary RP is characterized by elevations in plasma ET-1 and ADMA levels that may contribute to alterations in cutaneous microvascular function.

Objective measures of recruitable blood flow are of importance in angiogenesis trials. We validated a new PET-derived flow reserve (FR) measurement in healthy subjects and subjects with peripheral artery disease (PAD).Five healthy volunteers and 5 subjects with PAD underwent cannulation of the femoral artery and vein. Basal and maximal flow (100 micro g/kg/min of adenosine infused intraarterially) in the lower extremity was determined using thermodilution (TD) techniques. Subjects then underwent plethysmography (PL) followed by PET measurements of blood flow at the calf level. For the PET studies, a transmission scan followed by injection of 1.85 GBq (50 mCi) H(2)(15)O and dynamic scanning for 5 min were acquired in five 1-min frames. Regions of interest were drawn on successive PET image slices, and radioactivity was quantified from the first-minute scan after injection. FR for each of the 3 modalities was expressed as the ratio of adenosine to basal flow.PET-derived FR correlated strongly with TD (r = 0.82; P = 0.004) but not with PL (r = 0.17; P = 0.85). The mean average difference in FR between healthy volunteers and PAD subjects was 13.0 with PET and 4.5 with TD. The intra- and intersubject variability for PET expressed as the coefficient of variation was 10.5% and 29.0% for healthy subjects and 7.0% and 52.9% in PAD, respectively.As expected, FR was significantly lower in PAD subjects compared with healthy subjects as assessed with TD and PET but not with PL. PET-derived FR appears to be reproducible and generates sharper and higher indices of recruitable flow in healthy subjects and PAD. These findings have implications for the use of PET-derived FR as a sensitive index of recruitable flow in angiogenesis trials.

a Abstract: The products of nitric oxide synthase (NOS) and angiotensin-converting enzyme (ACE) play a critical role in determining vessel wall structure and function. Polymorphisms in both genes have been independently demonstrated to ine uence propensity to cardiovascular events. The purpose of this study was to determine the ine uence of the homozygous G849T(Glu298 ! Asp) polymorphism in NOS III on peripheral conduit artery endothelial function and to elucidate the modie er role, if any, of a common ACE polymorphism. Three hundred and ninety-seven consecutive subjects presenting to the cardiac catheteriz- ation laboratory of the University of Michigan over a period of 18 months were recruited. DNA was extracted and polymerase chain reaction (PCR) analysis for ACE and NOS polymorphisms performed. Patients with homozygosity for G849T at both loci (TT) who belong to DD and II ACE genotype (groups 1 and 2) and those who are negative for this polymorphism (GG) and belong to either DD or II genotype (groups 3 and 4) were identie ed. The four groups then underwent determination of conduit endothelial function. Heterozygosity of Glu298-Asp or the ID variant of the ACE were not studied. Median FMD value in the TT-DD group was 0.20 ( -3.17, 2.01) compared with 2.23% ( -0.29, 4.17) in the GG-II group. Median values in the TT-II and the GG-DD groups were 3.04 ( -1.16, 6.61) and 2.46% ( -1.83, 6.52) respectively. These values were not statistically signie cant ( p > 0.05 by one-way ANOVA). Median nitroglycerin-mediated dilation in the four groups did not differ between the four groups ( p = NS by ANOVA). Atherosclerosis burdens as assessed by angiography were not different across the groups. In conclusion, the homozygous NOS III variant (GG) status does not seem to interact addi- tively with the ACE homozygous DD genotype in determining e ow-mediated vasodilation in individuals with established atherosclerosis and pre-existent endothelial dysfunction.

Honoring Keith Griffin’s more than 40 years of fundamental contributions to the discipline of economics, the papers in this volume reflect his deep commitment to advancing the well-being of the world’s poor majority and his unflinching willingness to question conventional wisdom as to how this should be done.