CCL5/RANTES is a key chemoattractant released by degenerative intervertebral discs in organ culture.

Release of chemotactic factors in response to tissue damage has been described for different musculoskeletal tissues, including the intervertebral disc (IVD). This study investigated the chemoattractants that are released by induced degenerative IVDs and may be involved in recruiting mesenchymal stem cells (MSCs). Bovine caudal discs were cultured within a bioreactor and loaded under conditions that mimicked physiological or degenerative settings. Between days 4-6, medium was replaced by PBS, which was subsequently used for proteomic, ELISA and immunoprecipitation analyses of secreted chemokines and cytokines. A Boyden chamber assay was used to observe human MSC migration towards native and chemokine depleted media. Gene expression levels of chemokine receptors in human MSCs were analysed, and CCL5 was localised in bovine and human IVD by immunohistochemistry. Proteomic analysis revealed the presence of CCL5 and CXCL6 within conditioned media. Higher concentrations of CCL5 were found in the degenerative media, and a relationship was found between interleukin-1β and CCL5 concentration. Chemokine immunoprecipitation showed that MSCs had a significantly reduced chemotactic migration towards CCL5-immunoprecipitated and CCL5/CXCL6 co-immunoprecipitated media, whilst CXCL6 depletion did not change MSC chemotaxis. MSCs showed a significant increase in mRNA expression of the CCL5 receptors, CCR1 and CCR4, upon culture in degenerative media. Furthermore, CCL5 was identified in bovine and human disc tissue by immunohistochemistry. Hence, CCL5 may be a key chemoattractant that is produced and released by the intervertebral disc cells. Therefore, these factors could be used to enhance stem/progenitor cell mobilisation in regenerative therapies for early stages of disc degeneration.

Cell therapy for intervertebral disc repair: advancing cell therapy from bench to clinics

Intervertebral disc (IVD) degeneration is a major cause of pain and disability; yet therapeutic options are limited and treatment often remains unsatisfactory. In recent years, research activities have intensified in tissue engineering and regenerative medicine, and pre-clinical studies have demonstrated encouraging results. Nonetheless, the translation of new biological therapies into clinical practice faces substantial barriers. During the symposium "Where Science meets Clinics", sponsored by the AO Foundation and held in Davos, Switzerland, from September 5-7, 2013, hurdles for translation were outlined, and ways to overcome them were discussed. With respect to cell therapy for IVD repair, it is obvious that regenerative treatment is indicated at early stages of disc degeneration, before structural changes have occurred. It is envisaged that in the near future, screening techniques and non-invasive imaging methods will be available to detect early degenerative changes. The promises of cell therapy include a sustained effect on matrix synthesis, inflammation control, and prevention of angio- and neuro-genesis. Discogenic pain, originating from "black discs" or annular injury, prevention of adjacent segment disease, and prevention of post-discectomy syndrome were identified as prospective indications for cell therapy. Before such therapy can safely and effectively be introduced into clinics, the identification of the patient population and proper standardisation of diagnostic parameters and outcome measurements are indispensable. Furthermore, open questions regarding the optimal cell type and delivery method need to be resolved in order to overcome the safety concerns implied with certain procedures. Finally, appropriate large animal models and well-designed clinical studies will be required, particularly addressing safety aspects.

Una bella roba. ‘Novellare’ als Erzählkonzept in Boccaccios ›Decameron‹

Der narrative Entwurf von Boccaccios ›Decameron‹ und Boccaccios theoretische Reflexionen über das Erzählen stehen klar im Fluchtpunkt der horazischen Lehre des prodesse et delectare. Vor diesem Horizont entwickelt Boccaccio sein Konzept des novellare, das einerseits ein ‚Wiedererzählen’ (analog zu mhd. erniuwen) beinhaltet und andererseits zu einer neuen Autonomie des Erzählens vorstößt. Beobachten lässt sich dieser Vorgang des Erneuerns weniger in Boccaccios theoretischen Ausführungen (etwa im Schlusswort des ›Decameron‹ oder in den ›Genealogie deorum gentilium‹) als in seiner dichterischen Praxis. Als Schlüsseltext wird im Vortrag die Novelle von der duldsamen Griselda herangezogen, die das ›Decameron‹ beschließt und die mit den Worten una bella roba endet. Das ‚schöne Kleid’ ist einerseits traditionelle Dichtungsmetapher (im Horizont des investire bzw. integumentum), andererseits intradiegetischer Bestandteil des Erzähl-‚Stoffs’ der Novelle. Bei Boccaccio dürfte das Gewand der Griselda, zusammen mit deren wiederholt thematisierter Nacktheit, dazu dienen, eine in die Novelle verpackte stoische Lehre zu vergegenwärtigen, diese in eine Erzählung ‚einzukleiden’. Das Kleid der Griselda wird so zur ‚Pathosformel’ (in der Begrifflichkeit A. Warburgs) bzw. zum ‚Faltenwurf’ (in der Begrifflichkeit G. Didi-Hubermans), mithin zur Verkörperung eines ‚neuen Erzählens’, das sich (im Gegensatz etwa zu Dante) von metaphysischen Entwürfen emanzipiert und in der Autonomie sprachlicher Kunstfertigkeit, bis an die Grenzen des Erzählbaren gehend und didaktische Ansprüche überwindend, die Möglichkeiten literarischer Darstellung ausreizt. Von den Zeitgenossen wurde dieses Experiment zwar wahrgenommen, in seinen Dimensionen aber nur ansatzweise erkannt. Symptomatisch für diese Form der Rezeption ist Petrarcas lateinische Übersetzung der ›Griselda‹-Novelle (›Seniles‹, XVII,3), wobei der Verfasser – seinerseits die Kleidermetaphorik bemühend – das Übersetzen als ein stilo alio retexere auffasst und seine Version den (wohl vorwiegend männlich intendierten Lesern) als auf Gott hin orientierte Lehre anempfiehlt: ut legentes ad imitandam saltem femine constantiam excitarem, ut [...] hoc prestare Deo nostro audeant. Diese Rückführung von Boccaccios erzählerischem Wagnis ins Didaktische zeigt sich auch in der Rezeption von Petrarcas Übersetzung, durch welche die Novelle im Europa des 14. und 15. Jahrhunderts weite Verbreitung fand: In einer der Haupthandschriften von Chaucers ›Canterbury Tales‹, dem Hengwrt Manuscript (Aberystwyth, National Library of Wales), wird die auf der ›Griselda‹-Novelle aufbauende Erzählung des Scholaren (›The Clerk’s Tale‹) mit Bestandteilen aus Petrarcas Übersetzung glossiert; in einer Handschrift aus dem Besitz des Nürnberger Humanisten Hartmann Schedel (München, Bayerische Staatsbibliothek, Clm 504) wird Petrarcas Konzept des stilo alio retexere erläutert als: claram facere, nudare [...], aperire, wobei hier die in Boccaccios Novelle intradiegetisch enthaltene Spannung von ‚Einkleidung’ und ‚Nacktheit’ auf einer lehrhaften Ebene fortwirkt.

Incidence of descending aortic pathology and evaluation of the impact of thoracic endovascular aortic repair: a population-based study in England and Wales from 1999 to 2010

To investigate population trends in thoracic aortic disease (dissections and aneurysms) in England and Wales, with focus on the impact of thoracic endovascular aortic repair on procedure numbers and age at repair.

Prediction of outcome in patients with low-grade squamous intraepithelial lesions by fluorescence in situ hybridization analysis of human papillomavirus, TERC, and MYC

BACKGROUND Cytology is an excellent method with which to diagnose preinvasive lesions of the uterine cervix, but it suffers from limited specificity for clinically significant lesions. Supplementary methods might predict the natural course of the detected lesions. The objective of the current study was to test whether a multicolor fluorescence in situ hybridization (FISH) assay might help to stratify abnormal results of Papanicolaou tests. METHODS A total of 219 liquid-based cytology specimens of low-grade squamous intraepithelial lesions (LSIL), 49 atypical squamous cells of undetermined significance (ASCUS) specimens, 52 high-grade squamous intraepithelial lesion (HSIL) specimens, and 50 normal samples were assessed by FISH with probes for the human papillomavirus (HPV), MYC, and telomerase RNA component (TERC). Subtyping of HPV by polymerase chain reaction (PCR) was performed in a subset of cases (n=206). RESULTS There was a significant correlation found between HPV detection by FISH and PCR (P<.0001). In patients with LSILs, the presence of HPV detected by FISH was significantly associated with disease progression (P<.0001). An increased MYC and/or TERC gene copy number (>2 signals in>10% of cells) prevailed in 43% of ASCUS specimens and was more frequent in HSIL (85%) than in LSIL (33%) (HSIL vs LSIL: P<.0001). Increased TERC gene copy number was significantly correlated with progression of LSIL (P<.01; odds ratio, 7.44; area under the receiver operating characteristic curve, 0.73; positive predictive value, 0.30; negative predictive value, 0.94) CONCLUSIONS: The detection of HPV by FISH analysis is feasible in liquid-based cytology and is significantly correlated with HPV analysis by PCR. The analysis of TERC gene copy number may be useful for risk stratification in patients with LSIL.