Role of basic calcium phosphate crystals in osteoarthritis

L'arthrose est une maladie dégénérative des articulations due à une dégradation progressive du cartilage. La calcification de l'articulation (essentiellement due à des dépôts de cristaux de phosphate de calcium basique -cristaux BCP-) est une caractéristique de cette maladie. Cependant, le rôle des cristaux BCP reste à déterminer. Nous avons tout d'abord déterminé en utilisant des cultures primaires de chondrocytes que les cristaux de BCP induisaient la production de la cytokine IL-6, via une signalisation intracellulaire implicant les kinase Syk, PI3 et Jak et Stat3. Les cristaux de BCP induisent également la perte de protéoglycanes et l'expression de IL-6 dans des explants de cartlage humain et ces deux effets peuvent être bloqués par un inhibiteur de IL-6, le Tocilizumab. Par ailleurs, nous avons trouvé que l'IL-6 ajouté à des chondrocytes, favorisait la formation de cristax de BCP et augmentait l'expression de gènes impliqués dans le processus de minéralisation : Ank (codant pour un transporteur de pyrophooshate), Annexin5 (codant pour un canal calcique) et Pit-1 (codant pour un transporteur de phoshate). In vivo, les cristaux de BCP injectés dans l'articulation de souris induisent une érosion du cartilage. Dans un modèle murin d'arthrose du genou induit par ménisectomie, nous avons observé la formation progressive de cristaux de BCP. Fait intéressant, la présence de ces cristaux dans l'articulation précédait la destruction du cartilage. Un agent susceptible de bloquer les calcifications tel que le sodium thiosulfate (STS), administré à des souris ménisectomisées, inhibait le dépôt intra-articulaire de ces cristaux ainsi que l'érosion du cartilage. Nous avons identifié ainsi un cercle vicieux dans l'arthrose, les cristaux induisant l'interleukine-6 et l'interleukine-6 induisant la formation de ces cristaux. Nous avons étudié si on pouvait bloquer cette boucle cristaux de BCP-IL6 soit par des agents décalcifiants, soit par des inhibiteurs d'IL-6. In vitro, des anticorps anti IL- 6 ou des inhibiteurs de signalisation, inhibaient significativement IL-6 et la minéralisation induite par IL-6. De même le STS inhibait la formation de ces cristaux et la production de l'IL-6. Tout récemment, nous avons trouvé que des inhibiteurs de la xanthine oxidoréductase étaient aussi capables d'inhiber à la fois la production d'IL-6 et la minéralization des chondrocytes. Finalement, nous avons pu exclure un rôle du système IL-1 dans le modèle d'arthrose induite par ménisectomie, les souris déficientes pour IL-1a/ß, MyD88 et l'inflammasome NLRP3 n'étant pas protégées dans ce modèle d'arthrose. L'ensemble de nos résultats montre que les cristaux BCP sont pathogéniques dans l'arthrose et qu'un inhibiteur de minéralisation tel que le STS ou un inhibiteur de l'interleukine-6 constitueraient des nouvelles thérapies pour l'arthrose. -- Osteoarthritis (OA), the most common degenerative disorder of the joints, results from an imbalance between the breakdown and repair of the cartilage and surrounding articular structures. Joint calcification (essentially due to basic calcium phosphate (BCP) crystal deposition) is a characteristic feature of OA. However, the role of BCP crystal deposition in the pathogenesis of OA remains unclear[1][1]. We first demonstrated that in primary murine chondrocytes exogenous BCP crystals led to IL-6 up-modulation and that BCP crystal signaling pathways involved Syk and PI3 kinases, and also gp130 associated molecules, Jak2 and Stat3. BCP crystals also induced proteoglycan loss and IL-6 expression in human cartilage expiants, (which were significantly reduced by an IL-6 inhibitor). In addition, we found that in chondrocytes exogenous IL-6 promoted calcium-containing crystal formation and up- regulation of genes codifying for proteins involved in the calcification process: the inorganic pyrophosphate transport channel Ank, the calcium channel Annexinö and the sodium/phosphate cotransporter Piti. In vivo, BCP crystals injected into murine knee joints induced cartilage erosion. In the menisectomy model, increasing deposits, identified as BCP crystals, were progressively observed around the joint before cartilage erosion. These deposits strongly correlated with cartilage degradation and IL-6 expression. These results demonstrated that BCP crystals deposition and IL-6 production are mutually reinforcing in the osteoarthritic pathogenic process. We then investigated if we could block the BCP-IL6 loop by either targeting IL-6 production or BCP crystal deposits. Treatment of chondrocytes with anti-IL-6 antibodies or inhibitors of IL-6- signaling pathway significantly inhibited IL-6-induced crystal formation. Similarly, sodium thiosulfate (STS), a well-known systemic calcification inhibitor, decreased crystal deposition as well as HA-induced IL-6 secretion in chondrocytes and, in vivo, it decreased crystal deposits size and cartilage erosion in menisectomized knees. Interestingly, we also found that xanthine-oxidoreductase (XO) inhibitors inhibited both IL-6 production and calcium crystal depositis in chondrocytes. We began to unravel the mechanisms involved in this coordinate modulation of IL-6 and mineralization. STS inhibited Reactive Oxygen Species (ROS) generation and we are currently investigating whether XO represents a major source of ROS in chondrocyte mineralization. Finally, we ruled out that IL-1 activation/signaling plays a role in the murine model of OA induced by menisectomy, as IL-1a/ß, the IL-1 R associated molecule MyD88 and NLRP3 inflammasome deficient mice were not protected in this model of OA. Moreover TLR-1, -2, -4,-6 deficient mice had a phenotype similar to that of wild-type mice. Altogether our results demonstrated a self-amplification loop between BCP crystals deposition and IL-6 production, which represents an aggravating process in OA pathogenesis. As currently prescribed OA drugs are addressing OA symptoms,our results highlight a potential novel treatment strategy whereby inhibitors of calcium- containing crystal formation and IL-6 could be combined to form the basis of a disease modifying treatment and alter the course of OA.

A reappraisal of 'International Stratigraphic Lexicon' and the need for the creation named units critical catalogues

Analysis of stratigraphic terminology and classification, shows that time-related stratigraphic units, which by definition have a global extent, are the concern of international cornrnissions and committees of the intemational Union of Geological Sciences (IUGS) . In contrast, lithostratigraphic, and other closely related units, are regional in extent and are catalogued in the International Stratigraphic Lexicon (ISL), the last volume of which, was published in 1987. Tlie intemational Commission on Stratigraphy (ICS) is currently attempting to revitalize the publication of ISL, given that the information contained in published volumes has never been updated, and that there has been a significant increase in stratigraphic research in recent decades. The proliferation of named units in the South Pyrenean and Ebro Basin Paleogene is evaluated to illustrate the extent of the problem. Moreover, new approaches to stratigraphic analysis have led to the naming of genetic units according to similar guidelines followed in the naming of descnptive or lithostratigraphic units. This has led to considerable confusion. The proposal to revitalize the ISL is accepted as part of the solution, that should also include the publication of critica1 catalogues, and the creation of norms for genetic unit terminology.

Foreign-Medical-School Graduates object to the VISA Qualifiying Examination

To the editor; The Visa Qualifying Examination is a two-day test composed of approximately 950 multiple-choice questions conerneing the basic and clinical sciences....

Dual-Energy CT: Basic Principles, Technical Approaches, and Applications in Musculoskeletal Imaging (Part 1).

In recent years, technological advances have allowed manufacturers to implement dual-energy computed tomography (DECT) on clinical scanners. With its unique ability to differentiate basis materials by their atomic number, DECT has opened new perspectives in imaging. DECT has been used successfully in musculoskeletal imaging with applications ranging from detection, characterization, and quantification of crystal and iron deposits; to simulation of noncalcium (improving the visualization of bone marrow lesions) or noniodine images. Furthermore, the data acquired with DECT can be postprocessed to generate monoenergetic images of varying kiloelectron volts, providing new methods for image contrast optimization as well as metal artifact reduction. The first part of this article reviews the basic principles and technical aspects of DECT including radiation dose considerations. The second part focuses on applications of DECT to musculoskeletal imaging including gout and other crystal-induced arthropathies, virtual noncalcium images for the study of bone marrow lesions, the study of collagenous structures, applications in computed tomography arthrography, as well as the detection of hemosiderin and metal particles.

The Changing Face of Psychiatric Nursing –Care or Control?

This report has been written as part of the project “Toward improved quality – developing nurse’s continuing vocational training in hospitals and inpatient units”. Its overall goal is to ensure high quality, ethically appropriate and therapeutically effective interventions to enable nurses to manage distressed and disturbed patients in European psychiatric hospitals and inpatient units. In this large-scale, multinational projects there are all together six European countries involved: Finland, Ireland, England, Portugal, Italy and Lithuania. The project work plan were during autumn 2006 and spring 2007. The content of this publication was produced in the first stage of the project aiming to collect the preliminary source material for the project. The literature review was carried out in the project stage, providing the groundwork for the next steps for the project. This project aims to develop an interactive multinational portal with training material. Therefore, it is important to share an understanding of basic information, psychiatric nurse’s continuing vocational education, laws and ethical codes and patient restriction used in mental health care. In this publication, the purpose of the material produced here is to understand nurses’ educational need related to vocational continuing education and to be used in further project stages as an empirical data collection. The data were collected as a preliminary source material for latter phases where nurse’s perceptions of the current practice, nurse’s attitudes to mental illness, prevalence of use of seclusion room and existing and desired vocational training provision will be collected in six different European countries. The following organisations are involved in this project: University of Turku, Dublin City University, St. Vincent Hospital, National Council for the Professional Development of Nursing and Midwifery, University of Padova, Klaipeda College - Health Faculty, Klaipeda Psychiatric Hospital, Escola Superior de Enfermagem de Lisboa, Centro Hospitalar Psiquiátrico de Lisboa, Omnia Vocational Institution the Espoo Region, Kellokoski psychiatric hospital, Hyvinkää hospital area, Pirkanmaa Hospital District, Kingston University & St. George’s Medical School and South West London & St. George’s Mental Health NHS Trust. A wide variety of different countries, organisations and individuals in this project give us a strong confidence that theoretical, practical, ethical and political issues around the topic of interest will be taken account during this project lifetime. We are aware the content of this book will be partially outdated almost as soon as it has been published. We still hope that this publication will encourage nurses and different professions working in mental health care field to have a basic understanding of similarities and differences between different European countries related in mental health care. We also hope that this publication will inspirate and motivate nurses in maintaining and developing the quality of psychiatric care in Europe.

Dual-Energy CT: Basic Principles, Technical Approaches, and Applications in Musculoskeletal Imaging (Part 2).

In recent years, technological advances have allowed manufacturers to implement dual-energy computed tomography (DECT) on clinical scanners. With its unique ability to differentiate basis materials by their atomic number, DECT has opened new perspectives in imaging. DECT has been successfully used in musculoskeletal imaging with applications ranging from detection, characterization, and quantification of crystal and iron deposits, to simulation of noncalcium (improving the visualization of bone marrow lesions) or noniodine images. Furthermore, the data acquired with DECT can be postprocessed to generate monoenergetic images of varying kiloelectron volts, providing new methods for image contrast optimization as well as metal artifact reduction. The first part of this article reviews the basic principles and technical aspects of DECT including radiation dose considerations. The second part focuses on applications of DECT to musculoskeletal imaging including gout and other crystal-induced arthropathies, virtual noncalcium images for the study of bone marrow lesions, the study of collagenous structures, applications in computed tomography arthrography, as well as the detection of hemosiderin and metal particles.

Aerosol therapy in intensive and intermediate care units: prospective observation of 2808 critically ill patients.

PURPOSE: Unlike in the outpatient setting, delivery of aerosols to critically ill patients may be considered complex, particularly in ventilated patients, and benefits remain to be proven. Many factors influence aerosol delivery and recommendations exist, but little is known about knowledge translation into clinical practice. METHODS: Two-week cross-sectional study to assess the prevalence of aerosol therapy in 81 intensive and intermediate care units in 22 countries. All aerosols delivered to patients breathing spontaneously, ventilated invasively or noninvasively (NIV) were recorded, and drugs, devices, ventilator settings, circuit set-up, humidification and side effects were noted. RESULTS: A total of 9714 aerosols were administered to 678 of the 2808 admitted patients (24 %, CI95 22-26 %), whereas only 271 patients (10 %) were taking inhaled medication before admission. There were large variations among centers, from 0 to 57 %. Among intubated patients 22 % (n = 262) received aerosols, and 50 % (n = 149) of patients undergoing NIV, predominantly (75 %) inbetween NIV sessions. Bronchodilators (n = 7960) and corticosteroids (n = 1233) were the most frequently delivered drugs (88 % overall), predominantly but not exclusively (49 %) administered to patients with chronic airway disease. An anti-infectious drug was aerosolized 509 times (5 % of all aerosols) for nosocomial infections. Jet-nebulizers were the most frequently used device (56 %), followed by metered dose inhalers (23 %). Only 106 (<1 %) mild side effects were observed, despite frequent suboptimal set-ups such as an external gas supply of jet nebulizers for intubated patients. CONCLUSIONS: Aerosol therapy concerns every fourth critically ill patient and one-fifth of ventilated patients.

Tuotealustapohjaisen suunnittelun vaikutukset risteilijän suunnitteluaikatauluihin

Tuotealustapohjaisella suunnittelulla pyritään hyödyntämään jo kertaalleen hyväksi todettuja kokonaisuuksia ja moduuleja, joiden avulla voidaan nopeasti suunnitella uusia tuotteita. Tarkoituksena on suunnitella asiakkaan näkökulmasta monia erilaisia tuotteita jopa sarjatuotannon kustannustehokkuudella. Tutkimuksessa esitetään risteilijän tuotealustapohjainen suunnitteluprosessi. Lisäksi työn tavoitteena on tutkia uuden suunnitteluprosessin vaikutukset risteilijän suunnitteluaikatauluihin. Tutkimuksessa haastateltiin Turun telakan suunnitteluosaston ja kehitysosaston johtajia. Haastatteluilla selvitettiin nykyisen suunnitteluprosessin haasteita, joiden nähtiin erityisesti viivästyttävät suunnitteluaikatauluja. Keskeisiä haasteita ovat suunnitteluresurssien ylikuormitus ja suunnittelulaadun huonontuminen. Lisäksi kartoitettiin tavoitteet risteilijän tuotealustaratkaisulle ja suunnitteluaikataululle. Haastattelukierroksen pohjalta ja teoriaa soveltaen analysoitiin risteilijän modulaariseen tuotealustaan perustuva suunnitteluprosessi. Tätä suunnitteluprosessia tutkittiin edelleen case-tutkimuksessa jääasemien osalta, jossa haastateltiin kyseisten alueiden suunnittelijoita. Lisäksi case-tutkimuksessa verrattiin jääaseman ja baaripentterin perussuunnittelun vaiheita toisiinsa. Näistä saatuja tutkimustuloksia verrattiin hyttialueen vakioidun perussuunnitteluohjeen vaikutuksiin suunnitteluprosessissa. Onnistunut tuotealustapohjainen suunnittelu vaatii sitoutumista jokaisella organisaation tasolla, jotta tuotealustassa olevien vakioituja moduuleja myös käytettäisiin. Modulaarisesta toiminnasta siirtyminen tuotealustapohjaiseen suunnitteluun vaatii vakioituja moduuleja ja vakioituja rajapintoja risteilijässä. Case-tutkimuksessa ja johtopäätöksissä on todettu uuden suunnitteluprosessin lyhentävän ja tuovan kustannussäästöjä tuotteen valmistusprosessissa.

A transformada de Fourier em basic

In this paper we describe three computer programs in Basic language about the Fourier transform (FFT) which are available in the Internet site http://artemis.ffclrp.usp.br/SoftwareE.htm (in English) or http://artemis.ffclrp.usp.br/softwareP.htm (in Portuguese) since October 1998. Those are addresses to the Web Page of our Laboratory of Organic Synthesis. The programs can be downloaded and used by anyone who is interested on the subject. The texts, menus and captions in the programs are written in English.

Amyloid Beta Precursor Protein: Proper Credit for the Basic Biochemical Properties of the Most Studied Protein in the 21st Century

The amyloid precursor protein (APP) is mainly known for being the precursor of the ß-amyloid peptide, which accumulates in plaques found in the brain of Alzheimer's disease patients. Expression in different tissues and the degree of sequence identity among mammals indicate an essential and non-tissue specific physiological function. APP is anchored to the membrane and displays a single C-terminal intracellular domain and a longer N-terminal extracellular domain. The basic biochemical properties and the scattered data on research, not related to production of beta-amyloid peptide, suggest that the protein and the molecules resulting from APP proteolytic cleavage may act as adhesion factors, enzymes, hormones/neurotransmitters and/or protease inhibitors. APP deserves to be known for its quite notable properties and its physiological role(s).