LRP1 Has a Predominant Role in Production over Clearance of Aβ in a Mouse Model of Alzheimer's Disease.

The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD

The 1980 earthquake in southern Italy: rescue of trapped victims and mortality.

A retrospective survey was undertaken on the health effects of the 1980 earthquake in southern Italy. The study population included 3619 people living in 7 villages situated near the epicentre of the disaster. The overall casualty rate (dead and injured) was 19.7%. Nearly all the deaths (192/202) occurred among trapped people who died before they could be rescued. Eighty per cent of all the trapped people were extricated within 2 days, mostly without the use of sophisticated means. The probability of survival decreased sharply, the longer the time before extrication. The crude mortality during the 18 months following the earthquake was 19.0 per thousand among the injured people who received treatment, and 14.1 per thousand among non-injured people. After age standardization, there was no significant difference between these two figures and the expected mortality figures for the Italian population in normal times (14.4 per thousand). These results stress the importance of providing rescue activities in the first 48 hours after the impact. Strengthening the self-reliance of the community in disaster preparedness is suggested as the best way to improve the effectiveness of relief operations. In disaster-prone areas, training and education in methods of rescue should be an integral part of any primary health care programme

Global considerations for implementation of telemedicine

In Dec. 1989, the United Nations proclaimed the Decade 1990-1999 as the International Decade for Natural Disasters Reduction (IDNDR). The Decade identified a number of research programs. IDNDR, provides a unique opportunity to explore the potential offered by the emerging technologies, and to promote, develop, and support those technologies deemed adequate to make the next century a safer one, especially in the poorest countries of the world. But all this improvement cannot be accomplished in a vacuum. We must begin now to eliminate pitfalls and illusions. A new attitude must emerge. In the scope of reducing human damages resulting from disasters, we must reconsider the cross-cultural understanding, and reach a real awareness which combines humility with a sense of relativeness. Promoting the right context is essential to the mandate of the Decade

Registries of congenital anomalies: EUROCAT.

Congenital anomalies are one of the potential adverse effects of the environment on reproductive health. Registries of congenital anomalies are useful to detect abnormal frequencies, clusters, and trends. Such registries should meet a number of conditions, including an appropriate population denominator, an efficient system for collecting information, standardized diagnostic procedures, postmortem examinations of still-births, and linkage of records. The EUROCAT (European Registration of Congenital Anomalies and Twins) program is a Concerted Action of the Commission of the European Communities initiated in 1979. One of its objectives is the surveillance of congenital anomalies as related to environmental hazards. This surveillance system covers at present 350,000 births per year in 15 countries. A number of problems encountered in the development of EUROCAT and in the course of ongoing activities are reviewed: populations coverage, classification of malformations, coding, definition and coverage of late fetal death, registration of induced abortion, validation of diagnostic information, registration of late diagnosed cases, and maintenance of motivation in data collection. The issue of confidentiality and the need for strict safeguards for the protection of individual privacy are emphasized

Cumulative subgroup analysis to reduce waste in clinical research for individualised medicine

Background: Although subgroup analyses in clinical trials may provide evidence for individualised medicine, their conduct and interpretation remain controversial. Methods: Subgroup effect can be defined as the difference in treatment effect across patient subgroups. Cumulative subgroup analysis refers to a series of repeated pooling of subgroup effects after adding data from each of related trials chronologically, to investigate the accumulating evidence for subgroup effects. We illustrated the clinical relevance of cumulative subgroup analysis in two case studies using data from published individual patient data (IPD) meta-analyses. Computer simulations were also conducted to examine the statistical properties of cumulative subgroup analysis. Results: In case study 1, an IPD meta-analysis of 10 randomised trials (RCTs) on beta blockers for heart failure reported significant interaction of treatment effects with baseline rhythm. Cumulative subgroup analysis could have detected the subgroup effect 15 years earlier, with five fewer trials and 71% less patients, than the IPD meta-analysis which first reported it. Case study 2 involved an IPD meta-analysis of 11 RCTs on treatments for pulmonary arterial hypertension that reported significant subgroup effect by aetiology. Cumulative subgroup analysis could have detected the subgroup effect 6 years earlier, with three fewer trials and 40% less patients than the IPD meta-analysis. Computer simulations have indicated that cumulative subgroup analysis increases the statistical power and is not associated with inflated false positives. Conclusions: To reduce waste of research data, subgroup analyses in clinical trials should be more widely conducted and adequately reported so that cumulative subgroup analyses could be timely performed to inform clinical practice and further research

Injury epidemiology after the 2001 Gujarat earthquake in India: a retrospective analysis of injuries treated at a rural hospital in the Kutch district immediately after the disaster

The number of injured far exceeds those dead and the average injury to mortality ratio in earthquakes stands at 3:1. Immediate effective medical response significantly influences injury outcomes and thus the overall health impact of earthquakes. Inadequate or mismanagement of injuries may lead to disabilities. The lack of precise data from immediate aftermath is seen as a remarkable weak point in disaster epidemiology and warrants evidence generation.To analyze the epidemiology of injuries and the treatment imparted at a secondary rural hospital in the Kutch district, Gujarat, India following the January 26, 2001 earthquake.Discharge reports of patients admitted to the hospital over 10 weeks were analyzed retrospectively for earthquake-related injuries.Orthopedic injuries, (particularly fractures of the lower limbs) were predominant and serious injuries like head, chest, abdominal, and crush syndrome were minimal. Wound infections were reported in almost 20% of the admitted cases. Surgical procedures were more common than conservative treatment. The most frequently performed surgical procedures were open reduction with internal fixation and cleaning and debridement of contaminated wounds. Four secondary deaths and 102 transfers to tertiary care due to complications were reported.The injury epidemiology reported in this study is in general agreement with most other studies reporting injury epidemiology except higher incidence of distal orthopedic injuries particularly to the lower extremities. We also found that young males were more prone to sustaining injuries. These results warrant further research. Inconsistent data reporting procedures against the backdrop of inherent disaster data incompleteness calls for urgent standardization of reporting earthquake injuries for evidence-based response policy planning

Biomarkers in immunonutrition programme, is there still a need for new ones? A brief review

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Oxacillin sensitization of methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus pseudintermedius by antisense peptide nucleic acids in vitro

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Antibiotic resistance genes can be targeted by antisense agents, which can reduce their expression and thus restore cellular susceptibility to existing antibiotics. Antisense inhibitors can be gene and pathogen specific, or designed to inhibit a group of bacteria having conserved sequences within resistance genes. Here, we aimed to develop antisense peptide nucleic acids (PNAs) that could be used to effectively restore susceptibility to β-lactams in methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus pseudintermedius (MRSP). RESULTS: Antisense PNAs specific for conserved regions of the mobilisable gene mecA, and the growth essential gene, ftsZ, were designed. Clinical MRSA and MRSP strains of high oxacillin resistance were treated with PNAs and assayed for reduction in colony forming units on oxacillin plates, reduction in target gene mRNA levels, and cell size. Anti-mecA PNA at 7.5 and 2.5 μM reduced mecA mRNA in MRSA and MRSP (p < 0.05). At these PNA concentrations, 66 % of MRSA and 92 % of MRSP cells were killed by oxacillin (p < 0.01). Anti-ftsZ PNA at 7.5 and 2.5 μM reduced ftsZ mRNA in MRSA and MRSP, respectively (p ≤ 0.05). At these PNA concentrations, 86 % of MRSA cells and 95 % of MRSP cells were killed by oxacillin (p < 0.05). Anti-ftsZ PNAs resulted in swelling of bacterial cells. Scrambled PNA controls did not affect MRSA but sensitized MRSP moderately to oxacillin without affecting mRNA levels. CONCLUSIONS: The antisense PNAs effects observed provide in vitro proof of concept that this approach can be used to reverse β-lactam resistance in staphylococci. Further studies are warranted as clinical treatment alternatives are needed.Peer reviewedFinal Published versio

Autogestão: desafios políticos e metodológicos na incubação de empreendimentos econômicos solidários

After reviewing the historic origins of self-management in France and Brazil, this article questions people’s ability for selfmanagement, or the situation in which without a boss there is no viable society. It turns to Clastres to show that, if political power is an inherent need of social life, it does not need to be hierarchical. There is no innate human nature, but our specificity as human beings is precisely our ability to transform ourselves and the world. Self-management is a central concept of the Brazilian solidarity economics movement because it distances itself from capitalist and welfare relations and encourages radical democracy. Self-management has a multidimensional character (being social, economic, political and technical) and therefore, it is not enough to want to implant selfmanagement. It is also necessary to create the conditions for its realization. The article also reflects on the methodology of selfmanagement practiced by members of a university incubator of solidarity economics.Após sobrevoar origens históricas da autogestão na França e no Brasil, o texto questiona a capacidade de os homens se autogerirem, ou a situação de que sem chefe não há sociedade viável. Recorre a Clastres para mostrar que, se o poder político é uma necessidade inerente à vida social, ele não precisa ser hierárquico. Não há natureza humana em si, mas nossa especificidade como ser humano é justamente nossa capacidade de transformar a nós mesmos e ao mundo. Para o movimento da economia solidária brasileira, a autogestão é um conceito central, pois marca distância com as relações capitalistas, assistencialistas e acena por uma democracia radical. A autogestão possui um caráter multidimensional (social, econômico, político e técnico) e, portanto, não basta querer implantar a autogestão, ainda é preciso criar as condições para a sua efetivação. O artigo apresenta, ainda, uma reflexão sobre a metodologia autogestionária praticada pelos membros de uma incubadora universitária de economia solidária

Desafíos políticos de los países de inmigración

13 págs.-- Publicado en "Confluencia XXI. Revista de Pensamiento Político" (México), nº 3 (Oct-Dic 2008) bajo el título monográfico "Migrantes: ¿Por qué se van? ¿Por qué se quedan?".Las migraciones, una práctica tan antigua como la propia condición humana, se han convertido en un factor estructural de primer orden, en uno de los macrofenómenos más definitorios de nuestra época y en un complejo reto para las sociedades contemporáneas. En prácticamente todos los países del mundo, todo lo que concierne a este complejo fenómeno ocupa un lugar destacado en la agenda política. La gestión, el control y la integración de los movimientos internacionales de personas se presentan como un policy field de creciente y prioritaria relevancia. No se trata, sin embargo, de una cuestión de mera moda: el número de países implicados de manera significativa en las migraciones internacionales ha aumentado considerablemente, hasta el punto de que resulta realmente difícil encontrar algún Estado que no sea bien un país de inmigración, bien un país de emigración o bien ambas cosas a la vez, cuando no al menos un país de tránsito. No ha de extrañar entonces que la mayoría de los gobiernos haya tomado conciencia de la necesidad de ofrecer una respuesta en términos legales e institucionales a un fenómeno de carácter permanente que puede llegar a alterar la estructura demográfica, social, cultural, económica y laboral de un país. Dada la complejidad de la cuestión, y por cuestiones de economía argumentativa, aquí se abordará de manera fundamental desde la perspectiva de los países receptores, que, por lo demás, es también la adoptada en forma habitual por los países europeos que registran mayor inmigración. Sin embargo, el fenómeno migratorio es fundamentalmente transnacional y tiene fehacientes repercusiones en los países de emigración.Peer reviewe