Targeting early changes in the synovial microenvironment:a new class of immunomodulatory therapy?

Objectives: Controlled immune responses rely on integrated crosstalk between cells and their microenvironment. We investigated whether targeting proinflammatory signals from the extracellular matrix that persist during pathological inflammation provides a viable strategy to treat rheumatoid arthritis (RA). Methods: Monoclonal antibodies recognising the fibrinogen-like globe (FBG) of tenascin-C were generated by phage display. Clones that neutralised FBG activation of toll-like receptor 4 (TLR4), without impacting pathogenic TLR4 activation, were epitope mapped by crystallography. Antibodies stained synovial biopsies of patients at different stages of RA development. Antibody efficacy in preventing RA synovial cell cytokine release, and in modulating collagen-induced arthritis in rats, was assessed. Results: Tenascin-C is expressed early in the development of RA, even before disease diagnosis, with higher levels in the joints of people with synovitis who eventually developed RA than in people whose synovitis spontaneously resolved. Anti-FBG antibodies inhibited cytokine release by RA synovial cells and prevented disease progression and tissue destruction during collagen-induced arthritis. Conclusions: Early changes in the synovial microenvironment contribute to RA progression; blocking proinflammatory signals from the matrix can ameliorate experimental arthritis. These data highlight a new drug class that could offer early, disease-specific immune modulation in RA, without engendering global immune suppression

Abelard: Celebrity and Charisma—A Response to Dickson

One might think that Peter Abelard (1079?–1144?) would be the best example of a medieval charismatic teacher. But his rival and prosecutor St Bernard of Clairvaux (1090?–1153) fits the criteria rather better. Unlike Bernard, Abelard denied that he had sought out disciples. Nevertheless, he can be shown to have had student followers, even though some of them repudiated him. Abelard is most important as a public intellectual who depended on public institutions (the incipient university of Paris) rather than on private or monastic patronage

Literacy, Law, and the Power of the State

The author argues that writing promotes the interests of the State through the standardization it imposes on language and its users. In medieval culture as a whole the effects of such standardization are evident in the schooling of the clergy in Latin. In England in particular writing was the basis of the "Common Law" which gave uniformity to the Anglo-Norman kingdom in the twelfth century. Royal writs, available to all freemen, broke down feudal hierarchies and traditional procedures which had depended on oral custom. Writing automated the legal process by mass-producing royal orders in standardized forms. As a result, the king's authority, which had been essentially personal, was converted into the abstract power of the "Crown" governed by bureaucratic procedures. This is the genesis of the modern State.Clanchy Michael. Literacy, Law, and the Power of the State. In: Culture et idéologie dans la genèse de l'État moderne. Actes de la table ronde de Rome (15-17 octobre 1984) Rome : École Française de Rome, 1985. pp. 25-34. (Publications de l'École française de Rome, 82

Literacy, Law, and the Power of the State

The author argues that writing promotes the interests of the State through the standardization it imposes on language and its users. In medieval culture as a whole the effects of such standardization are evident in the schooling of the clergy in Latin. In England in particular writing was the basis of the "Common Law" which gave uniformity to the Anglo-Norman kingdom in the twelfth century. Royal writs, available to all freemen, broke down feudal hierarchies and traditional procedures which had depended on oral custom. Writing automated the legal process by mass-producing royal orders in standardized forms. As a result, the king's authority, which had been essentially personal, was converted into the abstract power of the "Crown" governed by bureaucratic procedures. This is the genesis of the modern State.Clanchy Michael. Literacy, Law, and the Power of the State. In: Culture et idéologie dans la genèse de l'État moderne. Actes de la table ronde de Rome (15-17 octobre 1984) Rome : École Française de Rome, 1985. pp. 25-34. (Publications de l'École française de Rome, 82

Les écritures ordinaires

Les écritures ordinaires présentent les interactions entre écrit et société médiévale, dans le nord de la France et l'espace des anciens Pays-Bas méridionaux, durant le long xiiie siècle. Essai autant que synthèse, ce livre original s'appuie sur une documentation richement illustrée et commentée. Il se propose de dégager les grandes lignes d'un moment clé de la révolution documentaire qui transforme le Moyen Âge, par des analyses codicologiques, diplomatiques et paléographiques. De plus en plus investis de valeur juridique, les documents du xiiie siècle deviennent aussi bien des instruments porteurs d'autorité que des écrits ordinaires, dégagés des formalismes, affranchis des cadres structurels diplomatiques, des normes et des règles. Cette masse grouillante d'écritures jette un éclairage nouveau sur la foule d'hommes et de femmes qui s'en emparent

Comparing research recruitment strategies to prospectively identify patients presenting with breathlessness in primary care

Two recruitment strategies for research were compared to prospectively identify patients with breathlessness who are awaiting a diagnosis in primary care. The first method utilised searches of the electronic patient record (EPR), the second method involved an electronic template triggered during a consultation. Using an electronic template triggered at the point of consultation increased recruitment to prospective research approximately nine-fold compared with searching for symptom codes and study mailouts

Feasibility study of a multicentre cluster randomised control trial to investigate the clinical and cost-effectiveness of a structured diagnostic pathway in primary care for chronic breathlessness: protocol paper

IntroductionChronic breathlessness is a common and debilitating symptom, associated with high healthcare use and reduced quality of life. Challenges and delays in diagnosis for people with chronic breathlessness frequently occur, leading to delayed access to therapies. The overarching hypothesis is a symptom-based approach to diagnosis in primary care would lead to earlier diagnosis, and therefore earlier treatment and improved longer-term outcomes including health-related quality of life. This study aims to establish the feasibility of a multicentre cluster randomised controlled trial to assess the clinical and cost-effectiveness of a structured diagnostic pathway for breathlessness in primary care.Methods and analysisTen general practitioner (GP) practices across Leicester and Leicestershire will be cluster randomised to either a structured diagnostic pathway (intervention) or usual care. The structured diagnostic pathway includes a panel of investigations within 1 month. Usual care will proceed with patient care as per normal practice. Eligibility criteria include patients presenting with chronic breathlessness for the first time, who are over 40 years old and without a pre-existing diagnosis for their symptoms. An electronic template triggered at the point of consultation with the GP will aid opportunistic recruitment in primary care. The primary outcome for this feasibility study is recruitment rate. Secondary outcome measures, including time to diagnosis, will be collected to help inform outcomes for the future trial and to assess the impact of an earlier diagnosis. These will include symptoms, health-related quality of life, exercise capacity, measures of frailty, physical activity and healthcare utilisation. The study will include nested qualitative interviews with patients and healthcare staff to understand the feasibility outcomes, explore what is ‘usual care’ and the study experience.Ethics and disseminationThe Research Ethics Committee Nottingham 1 has provided ethical approval for this research study (REC Reference: 19/EM/0201). Results from the study will be disseminated by presentations at relevant meetings and conferences including British Thoracic Society and Primary Care Respiratory Society, as well as by peer-reviewed publications and through patient presentations and newsletters to patients, where available.Trial registration numberISRCTN14483247

Viktor Krivulin. Concerto a richiesta e altre poesie, a cura di Marco Sabbatini

Prima raccolta antologica in italiano di Viktor Krivulin, con saggio introduttivo, nota bio-bibliografica, note ai testi e traduzioni a cura di Marco Sabbatin