Therapeutische Anwendung von Stammzellen in der Orthopädie

Stem cells are becoming increasingly more important in the field of regenerative medicine. Adult mesenchymal stem cells (MSCs) are harvested predominantly from bone marrow or adipose tissue, are already being used in the clinical setting and have a low potential for side effects. In orthopedics, experience has been gained in the treatment of bone defects, non-unions, cartilage defects, osteoarthritis and tendon pathologies. The current data are derived from case studies and randomized controlled trials are missing; therefore, there are many open questions concerning the optimal cell source, number of cells, administration technique (e.g. injections and matrices) or combinations with growth factors; however, it is evident from the data that MSCs have a positive effect on tissue regeneration and are safe to use.     

Modulation of in vitro eosinophil progenitors by hydrocortisone: role of accessory cells and interleukins

The growth of human eosinophil progenitors (CFU-Eo) and the modulation of growth by hydrocortisone were studied as functions of the presence of lymphocytes and monocytes in marrow cells under study; and the source of colony-stimulating factors, specifically, media conditioned by macrophage-like cell line, GCT; phytohemagglutinin-stimulated mononuclear cells (PHA-LCM); or the T cell line, MO. CFU-Eo growth was greatest in marrow containing accessory cells as compared to marrow depleted of accessory cells; and in marrow treated with phytohemagglutinin-stimulated leukocyte conditioned media (PHA-LCM) or MO (T cell line)-conditioned medium (MO-CM) as compared with GCT cell- conditioned medium (GCT-CM). Hydrocortisone reproducibly inhibited eosinophil progenitor growth in unfractionated marrow stimulated by GCT- CM. This effect was abrogated by admixing irradiated mononuclear cells or T lymphocytes with the target marrow or by adding interleukin 1 or interleukin 2 (IL-1, IL-2). Inhibition by hydrocortisone did not occur when monocyte and T lymphocyte depleted marrow was studied. Unlike GCT- CM, MO-CM and PHA-LCM stimulated equal proportions of eosinophil progenitors in nondepleted and accessory cell-depleted marrow and demonstrated less hydrocortisone inhibition. However, both GCT-CM and PHA-LCM produced in the presence of hydrocortisone stimulated significantly fewer CFU-Eos in both unfractionated and accessory cell- depleted marrow target populations. These results indicate that the growth of CFU-Eo and inhibition of growth by hydrocortisone is a direct function of a monocyte-T cell interaction and probably is mediated through effects on the production/release of eosinophil colony stimulating factor (Eo-CSF).     

Mucosal protection by sucralfate and its components in acid-exposed rabbit esophagus

Sucralfate has been reported to protect the esophageal epithelium of the rabbit and cat against acid injury. To determine the contribution of its components, aluminum hydroxide and sucrose octasulfate (SOS), rabbit esophageal epithelia were mounted in Ussing chambers to monitor changes in electrical resistance (R) upon exposure to HCl (pH 1.4-1.6). In untreated tissues, acidification of the luminal bath produced a progressive decline in R, indicating increased epithelial permeability. Sucralfate added to the luminal bath 45 min after acidification increased R to preexposure levels--an effect accompanied by increased luminal pH. Similar to sucralfate, aluminum hydroxide added to the acidified bath increased R and luminal pH. However, the effect of aluminum hydroxide could be abolished by titration with HCl to maintain pH similar to acid-treated control tissues. Tissues treated with sucralfate and whose luminal solutions were titrated with HCl to maintain pH similar to controls no longer exhibited an increase in R but, in contrast to aluminum hydroxide treatment, the acid-induced decline in R was prevented. This action of sucralfate was shown to be a property of its other component, SOS. Sucrose octasulfate, like acid-titrated sucralfate solutions, did not increase luminal bath pH, yet prevented the acid-induced decline in R. Confirmation of protection by SOS was shown by additional morphologic and flux studies. Thus 1 h after luminal bath acidification in the Ussing chamber, SOS-treated tissues demonstrated less damage (injury score 0.6 +/- 0.4 vs. 1.6 +/- 0.3, p less than 0.05) and lower permeability to mannitol (0.003 +/- 0.001 vs. 0.013 +/- 0.005 mumol/h X cm2, p less than 0.05) than untreated tissues. Similarly, 1 h of luminal perfusion with HCl in vivo produced less damage (injury score 1.3 +/- 0.5 vs. 3.5 +/- 0.4, p less than 0.05) and less H+ efflux from the lumen in SOS-treated than untreated tissues. These results indicate that sucralfate can protect against acid injury in esophagus and that this protection is mediated by (a) intraluminal pH buffering through its content of aluminum hydroxide and (b) enhancing mucosal defense against H+ entry and injury through its content of SOS.     

Papillarmuskelri? w?hrend eines Belastungs-EKGs nach Myokardinfarkt

The case of a 57 year old patient is reported, who suffered from an acute myocardial infarction with maximum CK and CKMB values of 821 and 84 U/l, respectively. The patient underwent bicycle exercise testing 9 days after a myocardial infarction in 25 W steps every 2 min starting with 50 W. The ergometry was interrupted at 125 W because of ST segment depression of 0.28 mV in V6. Systolic blood pressure dropped to 55 mm Hg, combined with severe angina and shock. Volume substitution and catecholamines did not elevate blood pressure. Immediate M-mode and Doppler echo revealed a "stiletto"-shaped mitral regurgitation profile typical of acute mitral valve insufficiency. The transesophageal echocardiogram showed a distinct mass moving between the left ventricle and left atrium, diagnostic of papillary muscle rupture. Despite of shock, mitral valve replacement was performed successfully. To our knowledge, this is the first report of a papillary muscle rupture during exercise testing after myocardial infarction. Papillary muscle rupture can be induced by exercise. This fateful event may not be predicted by the course of the ergometry. In case of hypotension during exercise, papillary muscle rupture should be considered. The diagnosis is to be established by transesophageal echocardiography.     

Serosal bicarbonate protects against acid injury to rabbit esophagus

The role of serosal bicarbonate ions (HCO3-) in protection against acid injury was investigated in rabbit esophageal mucosa mounted in Ussing chambers. Luminal acidification reduced potential difference and resistance in tissues exposed serosally to HCO3- or (unbuffered) HCO3-free solution. Whereas resistance declined similarly in both groups, potential difference declined less in HCO3- solution. After washout, HCO3-bathed tissues also had a greater increase in resistance, lower permeability to mannitol, and less histologic damage. Furthermore, as protection by HCO3- was not blocked by pretreatment with either the anion exchange blocker, 4 acetamido-4'-isothiocyanatostilbene 2-2'-disulfonic acid, or the carbonic anhydrase inhibitor, acetazolamide, and replacement of HCO3- with N-2-hydroxyethylpiperazine-N'-2-ethane sulfonic acid, a buffer impermeant to cells, was protective, an extracellular site for protection by HCO3- was likely. Where in the extracellular space HCO3- buffers H+ is unclear, but the absence of change in luminal pH and the inability to prevent the acid-induced increase in permeability in HCO3-bathed tissues argue against a luminal (preepithelial) site. Also, rapid repair was not demonstrated, indicating that a luminal site for protection after surface cell damage was unlikely. We conclude that serosal HCO3- is important in esophageal protection against acid damage by buffering H+ within the intercellular compartment of the extracellular space.     

CTGF expression is induced by TGF- beta in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis

Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF- beta) in connective tissue cells. CTGF can trigger many of the cellular processes underlying fibrosis, such as cell proliferation, adhesion, migration and the synthesis of extracellular matrix; however, its role in acute and chronic cardiac injury is not fully understood. Here, we show that TGF- beta is a specific inducer of CTGF expression in both cardiac fibroblasts and cardiac myocytes. The activity of a CTGF promoter-based reporter construct correlated with endogenous CTGF expression, suggesting that TGF- beta induces CTGF expression most likely by activating its promoter. Upregulation of CTGF coincided with an increase in fibronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF- beta induced CTGF expression and reduced the basal level of CTGF, whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF- beta induced CTGF expression. Furthermore, we found that both TGF- beta and CTGF mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well with concomitant increases in fibronectin, and type I and type III collagen mRNA levels in these animal hearts. Significant upregulation of CTGF was also detected in human heart samples derived from patients diagnosed with cardiac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF- beta signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis.