Interleukin-6 and chondrocyte mineralisation act in tandem to promote experimental osteoarthritis.

OBJECTIVES: Basic calcium phosphate (BCP) crystal and interleukin 6 (IL-6) have been implicated in osteoarthritis (OA). We hypothesise that these two factors may be linked in a reciprocal amplification loop which leads to OA. METHODS: Primary murine chondrocytes and human cartilage explants were incubated with hydroxyapatite (HA) crystals, a form of BCP, and the modulation of cytokines and matrix-degrading enzymes assayed. The ability of IL-6 to stimulate chondrocyte calcification was assessed in vitro. The mechanisms underlying the effects of HA on chondrocytes were investigated using chemical inhibitors, and the pathways mediating IL-6-induced calcification characterised by quantifying the expression of genes involved in chondrocyte mineralisation. The role of calcification in vivo was studied in the meniscectomy model of murine OA (MNX), and the link between IL-6 and cartilage degradation investigated by histology. RESULTS: In chondrocytes, BCP crystals stimulated IL-6 secretion, further amplified in an autocrine loop, through signalling pathways involving Syk and PI3 kinases, Jak2 and Stat3 molecules. Exogenous IL-6 promoted calcium-containing crystal formation and upregulation of genes involved in calcification: the pyrophosphate channel Ank, the calcium channel Annexin5 and the sodium/phosphate cotransporter Pit-1. Treatment of chondrocytes with IL-6 inhibitors significantly inhibited IL-6-induced crystal formation. In meniscectomised mice, increasing deposits of BCP crystals were observed around the joint and correlated with cartilage degradation and IL-6 expression. Finally, BCP crystals induced proteoglycan loss and IL-6 expression in human cartilage explants, which were reduced by an IL-6 inhibitor. CONCLUSIONS: BCP crystals and IL-6 form a positive feedback loop leading to OA. Targeting calcium-containing crystal formation and/or IL-6 are promising therapeutic strategies in OA.

Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice.

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.

Cytokine-induced sleep: Neurons respond to TNF with production of chemokines and increased expression of Homer1a in vitro.

Interactions of neurons with microglia may play a dominant role in sleep regulation. TNF may exert its somnogeneic effects by promoting attraction of microglia and their processes to the vicinity of dendrites and synapses. We found TNF to stimulate neurons (i) to produce CCL2, CCL7 and CXCL10, chemokines acting on mononuclear phagocytes and (ii) to stimulate the expression of the macrophage colony stimulating factor (M-CSF/Csf1), which leads to elongation of microglia processes. TNF may also act on neurons by affecting the expression of genes essential in sleep-wake behavior. The neuronal expression of Homer1a mRNA, increases during spontaneous and enforced periods of wakefulness. Mice with a deletion of Homer1a show a reduced wakefulness with increased non-rapid eye movement (NREM) sleep during the dark period. Recently the TNF-dependent increase of NREM sleep in the dark period of mice with CD40-induced immune activation was found to be associated with decreased expression of Homer1a. In the present study we investigated the effects of TNF and IL-1β on gene expression in cultures of the neuronal cell line HT22 and cortical neurons. TNF slightly increased the expression of Homer1a and IL-1β profoundly enhanced the expression of Early growth response 2 (Egr2). The data presented here indicate that the decreased expression of Homer1a, which was found in the dark period of mice with CD40-induced increase of NREM sleep is not due to inhibitory effects of TNF and IL-1β on the expression of Homer1a in neurons.

Care delivery value chains for ophthalmic clinics in Switzerland

Perceived patient value is often not aligned with the emerging expenses for health care services. In other words, the costs are often supposed as rising faster than the actual value for the patients. This fact is causing major concerns to governments, health plans, and individuals. Attempts to solve the problem have habitually been on the operational effectiveness side: increasing patient volume, minimizing costs, rationing, or closing hospitals, usually resulting in a zero-sum game. Only few approaches come from the strategic positioning side and "competition" among hospitals is still perceived rather as a danger than as a chance to create a positive-sum game and stimulate patient value. In their 2006 book, "Redefining Health Care", the renowned Harvard strategy professor Michael E. Porter and hospital management expert Professor Elizabeth Olmsted Teisberg approach the challenge from the positive-sum perspective: they propose to form Integrated Practice Units (IPUs) and manage hospitals in a modern, patient value oriented way. They argue that creating value-based competition on results should have the same effect on the health care sector like transparency and competition turned other industries with out-dated management models (like recently the inert telecommunication industry) into highly competitive and customer value creating businesses. The objective of this paper is to elaborate Care Delivery Value Chains for Integrated Practice Units in ophthalmic clinics and gather a first feedback from Swiss hospital managers, ophthalmologists, and patients, if such an approach could be a realistic way to improve health care management. First, Porter's definition of competitiveness (distinction between operational effectiveness and strategic positioning) is explained. Then, the Care Delivery Value Chain is introduced as a key element for understanding value-based management, followed by three practice examples for ophthalmic clinics. Finally, recommendations are given how the Care Delivery Value Chain can be managed efficiently and how the obstacles of becoming a patient-oriented organization can be overcome. The conclusion is that increased transparency and value-based competition on results has the potential to change the mindset of hospital managers-which will align patient value with the emerging health care expenses. Early adapters of this management approach will gain a competitive advantage. [Author, p. 6]

The First International Workshop on Warning Criteria for Active Slides: technical issues, problems and solutions for managing early warning systems

Early warning systems (EWSs) rely on the capacity to forecast a dangerous event with a certain amount of advance by defining warning criteria on which the safety of the population will depend. Monitoring of landslides is facilitated by new technologies, decreasing prices and easier data processing. At the same time, predicting the onset of a rapid failure or the sudden transition from slow to rapid failure and subsequent collapse, and its consequences is challenging for scientists that must deal with uncertainties and have limited tools to do so. Furthermore, EWS and warning criteria are becoming more and more a subject of concern between technical experts, researchers, stakeholders and decision makers responsible for the activation, enforcement and approval of civil protection actions. EWSs imply also a sharing of responsibilities which is often averted by technical staff, managers of technical offices and governing institutions. We organized the First International Workshop on Warning Criteria for Active Slides (IWWCAS) to promote sharing and networking among members from specialized institutions and relevant experts of EWS. In this paper, we summarize the event to stimulate discussion and collaboration between organizations dealing with the complex task of managing hazard and risk related to active slides.

O uso de calorimetria em ecologia

The macroscopic effects caused by sun radiation and the mankind-nature interactions in a ecosystem are firstly presented. However, the importance of calorimetric determinations to clarify some phenomena related to the living microorganism populations and their interactions with the food additive or inhibitor agents are reported. The collect values illustrate the occurence a great deal of effects in this microscopic world. For this subject, the reachest Latosol soil was selected due to the content of organic matter and consequently in microorganisms. Microbial activity was stimulated by addition of glucose, which showed to be the best nutrient source. Inhibitory effect was detected with many compounds used in the agriculture like some herbicides and fungicides. Although the assays are based on the use of the microcalorimetry, other techniques like respirometry contributes strongly to the understanding of the ecosystem. The main objective in this exposition is to stimulate by means of many interesting examples, the importance of preserving the environment in order to establish direct analogies by using the Chemistry in the daily life.

Quimiluminescência orgânica: alguns experimentos de demonstração para a sala de aula

The generation of "cold light", visible to the human eye, by chemical reactions has attracted the attention of the scientific community since the beginning of this century. Besides the academic interest in the elucidation of the mechanisms of excited state formations, many chemiluminescence reactions have found widespread analytical applications. Moreover, the phenomenon of chemiluminescence can also be used as a tool in undergraduate and college teaching. In this article, we describe several known chemiluminescence demonstrations, which are suitable for school teaching. The main objective of this work is to produce didactic material in Portuguese to stimulate Brazilian secondary and high school teachers to use these experiments in the classroom. The demonstrations include singlet oxygen emission, the luminol reaction, oscillating chemiluminescence and the peroxyoxalate reaction.

PK-YRITYKSET INNOVAATTOREINA : Satunnaisista parannuksista kohti innovaatioiden virtaa. Yhteenveto tutkimusraportista, 3/2009

Tämän tutkimuksen tarkoituksena oli selvittää, minkälaisia innovaatioita eri toimialojen pienissä yrityksissä on kehitetty ja minkälaisia kyvykkyyksiä se on edellyttänyt. Lisäksi tavoitteena oli selvittää, kuinka suotuisana ympäristönä yritykset kokivat oman alueensa ja miten alueiden kehittämistyö on vaikuttanut yritysten kykyyn kilpailla. Teoreettiset oletukset perustuvat aikaisempiin tutkimuksiin innovaatiojohtamisen, yrittäjyyden ja pk-yritysten liiketoiminnan kehittämisen alueilta. Empiirinen aineisto on kerätty sähköpostikyselyllä tuottaen 733 kriteerit täyttävää vastausta. Kyselytutkimusta edelsi neljän alueen tapaustutkimus, jonka aikana luotiin teoreettinen rakennelma pienten yritysten innovaatiokyvykkyyden arvioimiseksi. Tämän tutkimuksen aineisto ei tue yleistä väitettä, jonka mukaan innovaatiotoiminta olisi harvinaisempaa tai vähäisempää kooltaan pienemmissä yrityksissä. Kokoa enemmän näyttäisi vaikuttavan innovaatiotoiminnan luonne ja siihen kytkeytyvä kyvykkyys. Yritysten innovaatio-toiminnan luonteen ja laajuuden perusteella tuloksista nousee neljä erilaista innovaattoriprofiilia: satunnainen parantaja, jatkuva parantaja, radikaali uudistaja ja monipuolinen kehittäjä. Innovaatiokyvykkyyttä tutkittiin seitsemän eri osatekijän suhteen. Eri profiilit omaavien yritysten kyvykkyyden tasot erosivat toisistaan merkittävästi. Tulokset vahvistavat käsityksiä siitä, että yksittäisen kyvykkyystekijän sijaan kyvykkyyskombinaatio vaikuttaa enemmän innovatiotoiminnan monipuolisuuteen. Innovaatiotoiminnan lisääntyessä ja monipuolistuessa, yritysten kyvykkyys-vaatimukset kasvavat kaikkien osatekijöiden suhteen. Yritykset ovat tiedostaneet innovaatio-kyvykkyyden kehittämisen tarpeet. Kyvykkyys on ajuri, jonka kyydissä pienet ja suuret innovaatiot syntyvät. Tämä tutkimus suosittelee, että innovaatiokyvykkyyden kehittäminen nostetaan näkyväm-mäksi tavoitteeksi. Pienissä yrityksissä luontevin tapa vahvistaa kyvykkyyksiä on integroida se yrityksen kehittämistoimintaan johtaen itse itseään ruokkivaksi prosessiksi. Haasteelliset kehittämis-tavoitteet edellyttävät monipuolista kyvykkyyksien vahvistamista ja vahvistuneet kyvykkyydet mahdollistavat entistä haastavampien kehittämistavoitteiden asettamisen. Parhaimmillaan tämä prosessi johtaa pienelle yritykselle soveltuvaan onnistumisen spiraaliin, joka samanaikaisesti kiihdyttää sekä kyvykkyyksien että innovaatioiden kehittämistä - tuotoksena jatkuva ja monipuolinen innovaatioiden virta. Tulokset vahvistavat ensimmäisessa vaiheessa toteutetun tapaustutkimuksen havaintoja siitä, että alueiden kehittämistyöstä hyötyvät yritykset, joiden kyvykkyystekijät ovat entuudestaan korkeaa tasoa. Pitkälle tuotteistetut julkiset palvelut soveltuvat parhaiten suuremmille yrityksille, joissa kehittämistoiminta on projektoitu ja kehittämistyö tehdään erillisten resurssien turvin. Sitä vastoin, valtaosassa pieniä yrityksiä kehittämistyö tapahtuu tavanomaisen liiketoiminnan ohessa ja samoilla resursseilla. Alueet tarjoavat varsin runsaasti luonteeltaan epäjatkuvia palveluja kohdistuen yksittäisten kyvykkyystekijöiden parantamiseen tai prosessin yksittäiseen vaiheeseen, usein innovaatioprosessin alkupäähän radikaalin innovaation kehittämiseksi. Tämän kyselyn tulokset suosittelevat myös toista reittiä: vahvistetaan ensin yritysten innovaatiokyvykkyyttä jatkuvaan pieniä askelia ottavaan innovaatiotoimintaan, josta matka jatkuu radikaalien uudistusten kautta moni-puoliseksi kehittämiseksi.

O show da Química: motivando o interesse científico

The aim of this article is to provide the understanding of the chemical world that underlies everything around us by introducing basic chemical concepts and their everyday applications. The specific topics presented were selected according to their relevance and their ability to be presented as an exhibition. This format is based on the visual effects that help the public to see abstract descriptions in a concrete form. In addition, a soundtrack is used to stimulate the affective intelligence and relax the public. According to the results obtained here, we can conclude that chemical demonstrations, combined with music, help the presentation of scientific topics and motivate and facilitate the "chemistry communication".

Síntese de biodiesel: uma proposta contextualizada de experimento para laboratório de química geral

The contextualized understanding of concepts in Chemistry by students from other areas is a challenging task. In this experiment, the synthesis of biodiesel is done by base catalyzed transesterification of refined soy oil with methanol at room temperature and common glassware found in any chemistry laboratory. The proposal permits introducing several concepts, such as that of emulsion, viscosity and catalysis to illustrate an activity based on an actual problem. In this didactic approach, some common problems of biodiesel production, such as soap formation and phase separation, are introduced into the procedure in order to raise questions and motivate the students to participate in the experimental work and stimulate reflections about critical aspects of biodiesel production. This experiment was carried out in the first semester of 2006, in experimental general chemistry taken by physics and agricultural, civil and chemical engineering students of UNICAMP.

Inorganic Nanoparticles and the Immune System: Detection, Selective Activation and Tolerance

The immune system is the responsible for body integrity and prevention of external invasion. On one side, nanoparticles are no triggers that the immune system is prepared to detect, on the other side it is known that foreign bodies, not only bacteria, viruses and parasites, but also inorganic matter, can cause various pathologies such as silicosis, asbestosis or inflammatory reactions. Therefore, nanoparticles entering the body, after interaction with proteins, will be either recognized as self-agents or detected by the immune system, encompassing immunostimulation or immunosuppression responses. The nature of these interactions seems to be dictated not specially by the composition of the material but by modifications of NP coating (composition, surface charge and structure). Herein, we explore the use of gold nanoparticles as substrates to carry multifunctional ligands to manipulate the immune system in a controlled manner, from undetection to immunostimulation. Murine bone marrow macrophages can be activated with artificial nanometric objects consisting of a gold nanoparticle functionalized with peptides. In the presence of some conjugates, macrophage proliferation was stopped and pro-inflammatory cytokines were induced. The biochemical type of response depended on the type of conjugated peptide and was correlated with the degree of ordering in the peptide coating. These findings help to illustrate the basic requirements involved in medical NP conjugate design to either activate the immune system or hide from it, in order to reach their targets before being removed by phagocytes. Additionally, it opens up the possibility to modulate the immune response in order to suppress unwanted responses resulting from autoimmunity, or allergy or to stimulate protective responses against pathogens.

Governmental Measures to Enhance the Finnish Innovation System to Respond to the Challenge of Mitigating Climate Change

Climate innovations, that cover both technological applications and process and service innovations, play a key role in climate change mitigation. The purpose of this study was to examine how the Finnish innovation system could be enhanced with governmental measures so that the diffusion of climate innovations could be speeded up. During the study, it became evident that the governmental measures need to support the whole innovation chain, which comprises of research, development, demonstration and deployment. Only this can lead to the successful birth and diffusion of low carbon innovations. The study found that the strengths of the Finnish innovation system are research and development, and the current national innovation policies strongly support these activities. However, these have been emphasised at the expense of the demonstration and deployment. Consequently, the biggest bottlenecks in the Finnish innovation landscape are the lack of pilot and demonstration projects and slow commercialisation, thus the high price of the innovation. To meet with the challenge, the government should firstly promote strict greenhouse gas emission reduction targets. This would boost up the innovation activities, which would also lower the prices of the innovations. To speed up the commercialisation process, measures that stimulate the domestic market, such as feed-in-tariffs and public procurements, are needed. Special attention should also be paid to the measures that could shift the traditional closed innovation chain towards open innovation. This means that the product development should involve experts from several fields such as the user and marketing experts to speed up the commercialisation. In addition, efficient innovation co-operation between both private and public sector is essential. Finally, as the domestic resources are not adequate for producing all the innovations needed, the domestic innovation activities should be focused on a few sectors, and at the same time promote efficient import policies.

O papel governamental como ator essencial para a P&D de medicamentos: um estudo de casos

The importance of natural products as a source of new high value-added drugs has, no doubt, transformed Brazilian megadiversity into one of the country's most valuable and strategic assets. Thus the rational exploration of the Brazilian flora on an economic basis should be considered as part of a national development strategy. In this respect, governmental mechanisms to stimulate regulation on the access, bioprospection and industrial use of natural products represent a crucial issue. The aim of this paper is to show how the incentives and institutional arrangements that led to one of the greatest breakthroughs in the pharmaceutical industry, the development and commercialization of the anti-cancer agent Taxol, could be applied to the Brazilian case.

Um panorama da nanotecnologia no Brasil (e seus macro-desafios)

The objectives of this essay are to describe the development of nanoscience and nanotechnology (N&N) in Brazil. The analysis shows that Brazilian research in N&N is considered satisfactory and, although under other denominations, dates from at least 20 years. Innovation is still less satisfactory and there are different points of views on the issue. However, there is already a tendency towards the promotion of innovation in nanotechnology in the country. Scientists and the industrial sector have been showing interest in partnerships and some scientific policies stimulate this articulation between academy and companies.

Transformações biológicas: contribuições e perspectivas

In a moment that amazingly advances are being reached on the development of technologies to obtain high value chemical compounds as polymers, fine chemicals, pharmaceutical industry intermediates and chemical entities, we cannot refuse that a meaningful progress is due to the maturing in knowledge of biological transformations. Biocatalysis and biotransformations are being widespread applied to generate processes and products with incredible success. In this review article we present the main contributions of biotechnology and biological catalytic processes to Chemistry, the most important evolution steps on enzymatic transformations, how it has being applied and which are the perspectives to academic and industrial environments. We also would like to stimulate the community to step out research in biotechnology applicable to chemical and pharmaceutical industries, trying to achieve what we believe to be the ideal layout: integrating chemical transformations, enzymatic conversions and fermentation processes.