La apertura de un barrio: Las transformaciones del espacio urbano en Palermo, Buenos Aires = The Opening of a Neighborhood: The Transformations of Urban Space en Palermo, Buenos Aires

The transformations of neoliberalism in Latin America produced profound structural shifts throughout the urban environment. In Buenos Aires, Argentina certain neighborhoods became hotbeds for change. One neighborhood, Palermo, formerly a working class neighborhood, transformed into a neighborhood of distinct locales, each with its own name connected to another large world city, such as New York and London. These areas became deeply tied to international brands and markets, sourcing goods and businesses from all over the world. In addition, the area grew tremendously in the sectors of leisure, entertainment, and gastronomy. New shops, bars, discotheques, restaurants, and boutiques sprouted up in both new constructions brought on with the growth of real estate, and also in older, renovated buildings that remained from the epoch of workshops and factories. In this context, I explore the urban transformations in Palermo, a neighborhood located in the north of the city and also noted for being the largest of all districts in the capital. This paper explores issues of urban neoliberalism in the context of this neighborhood, making sense of new forms of fragmentation, in terms of the political, economic, and social sectors. As part of this fragmentation and rupture in the urban fabric, conflicts of social exclusion and gentrification have emerged alongside movements of resistance that are working to challenge the hegemonic nature of urban neoliberalism. The study, through a qualitative investigation in Palermo, Buenos Aires, Argentina, concludes that there have been profound structural changes in the urban environment and the composition of Palermo that point to deepening gentrification, social exclusion y marginalization throughout Buenos Aires. However, new forms of resistance and struggle within the neighborhood alongside growing academic insight have raised many criticisms and suggestions for changes in urban development

Constructing a Confidence Interval for the Fraction Who Benefit from Treatment, Using Randomized Trial Data

The fraction who benefit from treatment is the proportion of patients whose potential outcome under treatment is better than that under control. Inference on this parameter is challenging since it is only partially identifiable, even in our context of a randomized trial. We propose a new method for constructing a confidence interval for the fraction, when the outcome is ordinal or binary. Our confidence interval procedure is pointwise consistent. It does not require any assumptions about the joint distribution of the potential outcomes, although it has the flexibility to incorporate various user-defined assumptions. Unlike existing confidence interval methods for partially identifiable parameters (such as m-out-of-n bootstrap and subsampling), our method does not require selection of m or the subsample size. It is based on a stochastic optimization technique involving a second order, asymptotic approximation that, to the best of our knowledge, has not been applied to biomedical studies. This approximation leads to statistics that are solutions to quadratic programs, which can be computed efficiently using optimization tools. In simulation, our method attains the nominal coverage probability or higher, and can have substantially narrower average width than m-out-of-n bootstrap. We apply it to a trial of a new intervention for stroke

CCR2 and CXCR4 regulate peripheral blood monocyte pharmacodynamics and link to efficacy in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>CCR2 plays a key role in regulating monocyte trafficking to sites of inflammation and therefore has been the focus of much interest as a target for inflammatory disease.</p> <p>Methods</p> <p>Here we examined the effects of CCR2 blockade with a potent small molecule antagonist to determine the pharmacodynamic consequences on the peripheral blood monocyte compartment in the context of acute and chronic inflammatory processes.</p> <p>Results</p> <p>We demonstrate that CCR2 antagonism <it>in vivo </it>led to a rapid decrease in the number of circulating Ly6C^himonocytes and that this decrease was largely due to the CXCR4-dependent sequestration of these cells in the bone marrow, providing pharmacological evidence for a mechanism by which monocyte dynamics are regulated <it>in vivo</it>. CCR2 antagonism led to an accumulation of circulating CCL2 and CCL7 levels in the blood, indicating a role for CCR2 in regulating the levels of its ligands under homeostatic conditions. Finally, we show that the pharmacodynamic changes due to CCR2 antagonism were apparent after chronic dosing in mouse experimental autoimmune encephalomyelitis, a model in which CCR2 blockade demonstrated a dramatic reduction in disease severity, manifest in a reduced accumulation of monocytes and other cells in the CNS.</p> <p>Conclusion</p> <p>CCR2 antagonism <it>in vivo </it>has tractable pharmacodynamic effects that can be used to align target engagement with biologic effects on disease activity.</p

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0·771) was similar. Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status

EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer

Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin β family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output. Focal deletions of the RanBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM) and silencing of RanBP6 promoted glioma growth in vivo. Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway.This research was supported by the National Brain Tumor Society (I.K.M.), the National Institutes of Health grants 1R01NS080944-01 (I.K.M.), 1 R35 NS105109 01 (I.K.M.), and P30CA008748 (MSKCC Core Grant), the Geoffrey Beene Cancer Research Foundation (I.K.M.), the Cycle of Survival (I.K.M.), and the Seve Ballesteros Foundation (M.S.). B.O. was supported by an American–Italian Cancer Foundation fellowship and a MSKCC Brain Tumor Center grant. W.-Y.H. is the recipient of a FY15 Horizon Award from the U.S. Department of Defense (W81XWH-15-PRCRP-HA). A.C.-G. is the recipient of the Severo-Ochoa PhD fellowship. Further support was provided by the Sontag Foundation (B.S.T.). We thank all members of the Mellinghoff laboratory for helpful suggestions. We thank Dr. Fiona Ginty (Diagnostic Imaging and Biomedical Technologies, GE Global Research Center, Niskayuna, New York, USA) for assistance with multiplexed immunofluorescence. We thank A.J. Schuhmacher and C.S. Clemente-Troncone for assistance with the in vivo experiments, M. Kaufmann for assistance in the luciferase assays and N. Yannuzzi for assistance in cloning.S

A quantitative comparison of different methods to detect cardiorespiratory coordination during night-time sleep

BACKGROUND: The univariate approaches used to analyze heart rate variability have recently been extended by several bivariate approaches with respect to cardiorespiratory coordination. Some approaches are explicitly based on mathematical models which investigate the synchronization between weakly coupled complex systems. Others use an heuristic approach, i.e. characteristic features of both time series, to develop appropriate bivariate methods. OBJECTIVE: In this study six different methods used to analyze cardiorespiratory coordination have been quantitatively compared with respect to their performance (no. of sequences with cardiorespiratory coordination, no. of heart beats coordinated with respiration). Five of these approaches have been suggested in the recent literature whereas one method originates from older studies. RESULTS: The methods were applied to the simultaneous recordings of an electrocardiogram and a respiratory trace of 20 healthy subjects during night-time sleep from 0:00 to 6:00. The best temporal resolution and the highest number of coordinated heart beats were obtained with the analysis of 'Phase Recurrences'. Apart from the oldest method, all methods showed similar qualitative results although the quantities varied between the different approaches. In contrast, the oldest method detected considerably fewer coordinated heart beats since it only used part of the maximum amount of information available in each recording. CONCLUSIONS: The method of 'Phase Recurrences' should be the method of choice for the detection of cardiorespiratory coordination since it offers the best temporal resolution and the highest number of coordinated sequences and heart beats. Excluding the oldest method, the results of the heuristic approaches may also be interpreted in terms of the mathematical models