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Biomedical subjects

G Steinhoff

Publications and source records attributed to G Steinhoff.

At least 19 recordsLinked to original sources
PubMed2006

The effects of the dual 5alpha-reductase inhibitor dutasteride on localized prostate cancer--results from a 4-month pre-radical prostatectomy study.

BACKGROUND: As dihydrotestosterone (DHT) is the most potent androgen in the prostate, inhibition of the 5alpha-reductase isoenzymes, which convert testosterone to DHT, could be an appropriate target for the treatment of prostate cancer. METHODS: Eighty-one men with clinically localized prostate cancer received daily dutasteride 3.5 or 0.5 mg, or no therapy for 4 months before radical prostatectomy. Histopathological assessments were conducted on prostatectomy specimens. RESULTS: Treatment with dutasteride was associated with reductions in serum and intraprostatic DHT of >or=90%, and a decrease in total prostate and tumor volumes. No effect of dutasteride was noted on Gleason grade. Histopathological effects on benign tissue were similar but less prominent than those seen with androgen ablation, whereas there was no significant difference in cancer histology among the groups. CONCLUSIONS: Dutasteride treatment results in similar but less marked changes compared with androgen ablation.

5-alpha Reductase Inhibitors↗
PubMed2006

Endothelial nitric oxide synthase mediates protective effects of hypoxic preconditioning in lungs.

To elucidate the protective mechanism of whole-body hypoxic preconditioning (WHPC) on pulmonary ischemia-reperfusion injury focussing on nitric oxide synthases (NOS), mice were placed in a hypoxic chamber (FIO(2)=0.1) for 4h followed by 12h of normoxia. Then, pulmonary ischemia for 1h followed by 5h of reperfusion was performed by clamping the left hilum in vivo (I/R). WHPC protected WT mice from pulmonary leukocyte infiltration as assessed by myeloperoxidase (MPO) activity, associated with a mild further increase in endothelial permeability (Evans Blue extravasation). When all NOS isoforms were inhibited during WHPC by L-NAME, mortality and MPO activity after I/R markedly increased. To determine the responsible NOS isoform, quantitative RT-PCR was performed for eNOS and iNOS mRNA, showing that only eNOS was upregulated in response to WHPC. While eNOS total protein expression remained unchanged, the amount of phosphorylated eNOS also increased. The WHPC/IR experiments were then repeated with eNOS knockout mice. Here, we found that the protective effect of WHPC on pulmonary leukocyte sequestration was abrogated, and endothelial leakage was further exacerbated. We conclude that WHPC limits neutrophil sequestration via an eNOS-dependent mechanism, and that eNOS helps preserve endothelial permeability during hypoxia and I/R.

Animals↗
PubMed2006

Effect of closed minimized cardiopulmonary bypass on cerebral tissue oxygenation and microembolization.

OBJECTIVE: Coronary artery bypass grafting with cardiopulmonary bypass carries a risk for neurologic complications because of cerebral hypoperfusion and microembolization. The basic goals of a novel closed minimized extracorporeal circulation are to prevent excessive hemodilution and to avoid blood-air interface. The aim of this prospective randomized study was to determine the effect of using the minimized extracorporeal circulation system compared with open conventional extracorporeal circulation on cerebral tissue oxygenation and microembolization. METHODS: Forty patients undergoing coronary artery bypass grafting (20 in each group) were continuously monitored for changes in cerebral oxygenated hemoglobin and tissue oxygenation index by using near-infrared spectroscopy. Total microembolic count and gaseous embolic count in both median cerebral arteries were monitored with multifrequency transcranial Doppler instrumentation. RESULTS: In the conventional extracorporeal circulation group there was a highly significant reduction in both cerebral oxygenated hemoglobin and tissue oxygenation index from the start to the end of cardiopulmonary bypass (P < .01). The rate of decrease in cerebral oxygenated hemoglobin after aortic cannulation was faster in the conventional extracorporeal circulation group (F test = 9.03, P < .001). No significant changes with respect to cerebral oxygenated hemoglobin or tissue oxygenation index occurred in the minimized extracorporeal circulation group, except at the beginning of rewarming (P < .01). Total embolic count, as well as gaseous embolic count, in the left and right median cerebral arteries was significantly lower in the minimized extracorporeal circulation group (all P < .05). Postoperative bleeding was greater (P < .05) and the transfusion rate was higher (P < .05) in the conventional extracorporeal circulation group. CONCLUSIONS: Use of closed minimized cardiopulmonary bypass compared with conventional open cardiopulmonary bypass preserves cerebral tissue oxygenation and reduces cerebral microembolization.

Aged↗
PubMed2006

[Stem cell therapy for the regeneration of heart muscle].

The loss of contractile heart tissue - often a sequelae of cardiac infarction - is caused by the limited regeneration capacity of the heart and usually leads to irreversible organ damage. Modification of this regeneration capacity by cell-based cardiac therapies with precursor and stem cells opens a new therapeutic field. A number of different (stem)cell types and applications are currently being evaluated. The possibilities and risks of the therapy are not easily foreseeable, however, clinical applications are already visible. In the light of stem cell research, the vision of regrowth of the heart in analogy to the Prometheus saga is obtaining a scientific explanation and may lead to new cardiac therapies.

Bone Marrow Transplantation↗
PubMed2006

Umbilical cord blood cell transplantation for myocardial regeneration.

Bone marrow remains the most frequently used source of adult stem cells, but its angiogenic and possibly also myogenic potentials are likely to regress with increasing donor age and morbidity. Recently, cord blood has been suggested as a readily available source for non-embryonic stem cells with high regenerative capacity. We first tested the capacity of mononuclear cells obtained from human umbilical cord blood (UCB(mn)) to migrate to the heart on IV delivery in NOD/Scid mice. As evidenced by the presence of human DNA by PCR analysis, UCB(mn) cells migrated to the heart in 50% of the mice with myocardial infarctions, but in none of the sham-operated control mice. In UCB(mn) cell-positive injured hearts, the infarct size was smaller and capillary density higher in the ischemic myocardium. By immunohistology, we observed endothelial cell differentiation of UCB(mn) cells in the heart but there was no colocalization of UCB cell-specific antibodies with markers of myocyte-type cells. In a second series of experiments, we injected 5 x 10(5) UCB cells enriched for CD133 directly into the necrotic myocardium of NOD/Scid mice. Comparisons were performed with an equivalent number of CD133+ bone marrow (BM) cells or a sham injection in the respective control groups. Both BMCD133+ and UCBCD133+ cells abolished postoperative mortality and improved capillary density in the injured myocardium, but only BMCD133+ cells led to a detectable improvement in myocardial contractility in vivo. We conclude that human UCB cells facilitated neovascularization of ischemic myocardium, but their capacity for formation of contractile neotissue needs further investigation.

Animals↗
PubMed2006

Cytomegalovirus and proliferative signals in the vascular wall of CABG patients.

OBJECTIVE: To further elucidate the mechanism by which cytomegalovirus (CMV) may promote atherosclerosis, we studied the expression pattern of cellular inflammatory and proliferative signals in the aortic wall of CMV(+) and CMV(-) patients undergoing coronary artery bypass grafting (CABG). METHODS: Aortic biopsies and blood samples of 68 CABG patients were investigated for CMV-DNA by PCR and IN SITU hybridisation. Expression of pp65 antigen, adhesion molecules (ICAM-1, VCAM-1, E-selectin), growth factors (PDGF-AA, TGF-beta), and the cellular proliferation factor Ki-67 was studied by immunohistochemistry. Logistic regression was used to test the correlation between the presence of CMV, vascular inflammation, and traditional noninflammatory risk factors for atherosclerosis. RESULTS: CMV-DNA was detected in the aortic tissue of 52 (76%) patients, and was localised predominantly in vascular smooth muscle cells. In CMV(+) patients, the expression of adhesion molecules and growth factors in the aortic endothelium was increased compared with CMV(-) patients. A positive correlation of elevated CRP, the induction of adhesion molecules and growth factors and CMV(+) was found. Female gender, smoking, and hyperlipidaemia were identified as risk factors for CMV(+). CONCLUSIONS: CMV-DNA in smooth muscle cells induces local growth factor expression as well as endothelial activation, both of which can promote the progression of atherosclerosis. Since traditional atherogenic risk factors increase the likelihood of aortic CMV manifestation, we suggest that CMV plays a crucial role in mediating the progression of atherosclerosis.

Aged↗
PubMed2004

Predicting the risk of early atherosclerotic disease development in children after repair of aortic coarctation.

AIMS: Increased cardiovascular morbidity is manifested a long time after the repair of aortic coarctation (CoA). By way of impaired flow-mediated vasodilation (FMD) and increased intima media thickness (IMT), surrogate parameters of atherosclerosis, cardiovascular risk factors (RFs) can be correlated with early vascular wall changes in children. This study investigated whether changes in arterial wall function and morphology are detectable in children after coarctation repair. METHODS AND RESULTS: We examined 28 children after successful repair of CoA vs. 30 control subjects. All children underwent identical screening, with a broad RF profile and FMD/IMT measurements. CoA-children presented significantly (P < 0.001) impaired FMD (4.87 +/- 2.6 vs. 10.2 +/- 3.1%) and higher IMT values (P < 0.001) than the controls (0.48 +/- 0.08 vs. 0.38 +/- 0.05 mm). The blood pressure during rest and exercise and the left ventricular mass were significantly elevated, but no additional RF could be identified in CoA-children. Only a remaining pressure gradient related significantly to FMD. CONCLUSION: This study documents early vascular wall changes in children after successful coarctation repair. Arterial hypertension and a resting pressure gradient are the major contributing factors to early atherosclerotic development and should be primary targets for therapy. Vascular status should be monitored regularly by FMD and IMT.

Adolescent↗
PubMed2004

Use of a fibrin preparation in the engineering of a vascular graft model.

OBJECTIVE: Morphological and functional characterization of cocultured endothelial cells (EC) and myofibroblasts (MFB) seeded on a matrix composed of a fibrin preparation mimicking the microenvironment of a vascular wall. METHODS: MFB and EC were isolated from human saphenous veins and expanded separately in vitro. MFB were seeded on a composite matrix consisting of a fibrin preparation (with or without transforming growth factor-beta2) and a polyglactin-mesh to form a 3-dimensional structure, which was consecutively reseeded with EC. Seeded matrices were incubated in a bioreactor. Characterization was done including fluorescence staining, live-/dead-assay and immunohistochemistry. RESULTS: High density cocultures in hierarchical structure mimicking the formation of a vascular wall were obtained with nearly complete coverage of the surface with EC. Distribution of preseeded MFB in a 519+/-27 microm thick layer (day 14) was achieved. Cell viability was shown in fluorescence staining for at least 19 days. In deeper layers, no viable cells could be detected within the fibrin preparation. EC covered the surface, had uniform morphology, and their preserved viability was shown for at least 5 days. No EC-ingrowth was found into the fibrin preparation. Neoformation of the matrix proteins laminin and collagen IV was observed. CONCLUSION: A structured coculture of MFB and EC was obtained mimicking the formation of a vascular wall with preserved viability utilizing a fibrin preparation. Nutrition problems seem to limit the maximal extent of MFB in the matrix.

Blood Vessels↗
PubMed2004

CABG and bone marrow stem cell transplantation after myocardial infarction.

OBJECTIVE: Bone marrow-derived adult stem cells may be able to regenerate infarcted myocardium. We initiated a phase-I study of autologous stem cell transplantation in patients undergoing coronary artery bypass grafting. METHODS: Inclusion criteria were: acute myocardial infarction > 10 days ago; presence of a distinct area of infarcted and akinetic myocardium; CABG indicated to treat ischemia of other LV wall areas. Stem cells were isolated from bone marrow using a ferrite-conjugated AC133 antibody, and were injected in the infarct border zone during the CABG operation. RESULTS: To date, 12 patients were treated without major complications. There is no evidence of new ventricular arrhythmia or neoplasia. Scintigraphic imaging demonstrated significantly improved local perfusion in the stem cell-treated infarct area. LV dimensions (LVEDV 140 +/- 38 ml vs. 124 +/- 30 ml, p = 0.004, paired t-test) and LV ejection fraction (39.7 +/- 9 % vs. 48.7 +/- 6 %, p = 0.007) have improved. CONCLUSIONS: Bone marrow stem cell transplantation for myocardial regeneration can be safely performed in humans. There is evidence of improved revascularization and contractility of infarct areas, but controlled studies are needed to clearly determine the clinical benefit.

Aged↗
PubMed2003

No evidence for productive PERV infection of baboon cells in in vivo infection model.

OBJECTIVES: The discovery that pig endogenous retroviruses are infectious for human cells in vitro lead to vehement discussions about the possible risk of infection after clinical xenotransplantation. Since PERV transmission to non-human primate cells in vitro has been observed, similar to human cells, infection studies in non-human primates should represent the best model to analyze a potential PERV transmission after xenotransplantation. However, it is still open to discussion, whether non-human primate cells can be infected productively-similar to human cells- and whether those species are suitable to analyze PERV infection risks in vivo. METHODS: In vitro, only few cell types can be tested for susceptibility. We developed a pig to baboon cell transplantation model with special emphasis on B-cell effective immunosuppression, removal of anti Gal-alpha 1,3-Gal-antibodies, inhibition of the complement cascade and long term survival of transplanted cellular grafts. This model allows us to investigate in vivo, whether any baboon cell types may be permissive for productive PERV infection. The xenograft recipients were investigated for up to 535 days post transplantation. Gal-alpha 1,3-Gal-antibody and complement levels were monitored. Potential PERV transmission was analyzed, not only in PBMC, but in a variety of tissue samples as well as in serum and plasma samples by PCR, RT-PCR and by detection of RT-activity. Moreover, potential PERV specific immune responses were studied by a highly sensitive Western-Blot-assay. RESULTS: Despite several days of extremely low levels of Gal-alpha 1,3-Gal-antibody and complement, and despite of long term xenochimerism, no evidence for PERV infection was obtained in any of the tested tissues or in the tested serum samples. CONCLUSION: This study supplies further evidence for a low susceptibility of baboons towards productive PERV infection after xenotransplantation.

Animals↗
PubMed2002

The efficacy of chondroitin sulfate 0.2% in treating interstitial cystitis.

OBJECTIVE: An open label study of chondroitin sulfate was undertaken to determine the response of patients with interstitial cystitis and positive potassium test results to this agent. METHOD: Eighteen patients with classic features of interstitial cystitis were enrolled in the study. Patients received 40 mL chondroitin sulfate, 0.2% instilled intravesically once a week for four weeks and then once a month for 12 months. At the same times, Quality of Life Improvement scores, voiding diaries, and pain and voiding indices were reviewed. RESULTS: Thirteen of 18 patients were followed for the entire 13-month study. Twelve of these patients responded to treatment within 3 to 12 weeks, on average. A total of 6/13 (46.2%) showed a good response, 2/13 (15.4%) had a fair response, and 4/13 (30.8%) had a partial response and 1/13 (7.7%) showed no response. CONCLUSION: Intravesical chondroitin sulfate seems to demonstrate some beneficial effects in treatment of interstitial cystitis patients who have positive potassium stimulation test results.

Chondroitin Sulfates↗
PubMed2002

Induction of long-term peripheral microchimerism in non-human primates in a model of xenogeneic peripheral tolerance induction.

Xenotransplantation represents a promising solution to the ever increasing shortage of donor organs in allotransplantation. However, due to different and stronger modes of rejection, successful xenotransplantation will require different organ-protective regimes from those used in allogeneic transplantation today. Since one can not simply increase the dosage of the drugs used, immunomodulation or tolerance induction of the recipient would be the most desirable approach. Transfusion of donor leukocytes has been shown to downregulate recipient responses or even induce peripheral tolerance in small animal models. Since the infusion of donor cells represents a relatively simple approach, as one can purify and compose the inoculum exactly before infusion, we studied whether this approach can be successfully employed in a preclinical swine to non-human primate model of peripheral tolerance induction/immunomodulation. In our model, baboons underwent sequential column adsorption and complement blockade. The animals received only initial immunosuppression with cyclophosphamide. No further immunosuppression was given. Subsequently all animals received 1-3 x 10(10) porcine splenocytes i.v. Development and maintenance of chimerism was analyzed by sequential flow cytometric and PCR analyses. Other parameters studied included effects of the preparatory induction protocol. We could show that a low level of chimerism is maintained in these animals for up to 1.5 years, despite the fact that they received no additional immunosuppression after the initial one. At no time of the experiment did any animal display symptoms of poor health. Thus we demonstrate that the concept of donor leukocyte transfusion is transferable into preclinical xenotransplantation. We are currently conducting organ transplantation experiments into animals thus treated to directly analyze the immunomodulatory effect of the donor cells.

Animals↗
PubMed2001

Analysis of potential porcine endogenous retrovirus (PERV) transmission in a whole-organ xenotransplantation model without interfering microchimerism.

The question whether porcine xenografts can lead to porcine endogenous retrovirus (PERV) infection of recipients is critical for the evaluation of the safety of pig-to-man xenotransplantation. Unfortunately, polymerase chain reaction (PCR)-based analysis of potential PERV infections in nonhuman-primate whole-organ xenotransplantation models is hampered by false positive results due to chimeric porcine cells. To avoid the inherent analytical problem of xenomicrochimerism, we developed a non-life-supporting pig-to-primate kidney xenotransplantation model: porcine kidneys were transplanted, whereas the functioning recipient kidneys remained in situ. Subsequent to rejection (after 2 hours to 15 days), xenografts were removed, and recipients remained alive for up to 287 days. Immunosuppressive therapy based on cyclophosphamide, cyclosporine, and steroids was maintained for 28 days after transplantation. Using appropriate PCR assays, xenochimerism was found in tissue samples and partly even in peripheral blood leukocytes (PBLs) while the porcine kidneys were in situ. After graft removal, xenochimerism was no longer detectable, thus allowing analysis for possible PERV transmission.

Animals↗
PubMed2001

Evaluation of different minimally invasive techniques in pediatric cardiac surgery: is a full sternotomy always a necessity?

STUDY OBJECTIVES: A variety of minimally invasive techniques have been recently introduced in adult cardiac surgery. Experiences with children and newborns are, however, limited. In this report, we present our first experiences with different methods of ministernotomies for closure of atrial septum defect (ASD) and ventricular septum defect (VSD) in pediatric cardiac patients. Also, the current literature for different surgical approaches is reviewed. PATIENTS AND METHODS: Twenty-five pediatric patients (range, 4 months to 12 years old) underwent elective ASD or VSD closure. Surgical access was either without division of the sternum (group A, n = 5), with partial inferior sternotomy (group B, n = 5), total sternotomy with limited skin incision (group C, n = 5), or total sternotomy with full skin incision (group D, n = 10). RESULTS: There were no severe intraoperative complications regarding exposure, cannulation, or bleeding. Conversion to full sternotomy was not necessary in any patient. Bypass time and cross-clamp time in groups A, B, and C were comparable to the standard operation (group D). However, preparation time was significantly increased in one minimally invasive group (group A vs group D, p<0.05). Despite general feasibility, the transxiphoidal access without sternotomy compromises exposure of the ascending aorta, resulting in impaired administration of cross-clamping, cardioplegia, and especially de-airing. CONCLUSIONS: Transatrial pediatric cardiac operations can be performed without or with limited sternotomy. The partial sternotomy allows uncompromised exposure of the great vessels and should be favored over the transxiphoidal approach. The operative access and perioperative risk is comparable to a classical standard surgical approach. Advantages include improved cosmetic results in combination with a high degree of safety.

Cardiac Surgical Procedures↗
PubMed2000

Tissue engineering of pulmonary heart valves on allogenic acellular matrix conduits: in vivo restoration of valve tissue.

BACKGROUND: Tissue engineering using in vitro-cultivated autologous vascular wall cells is a new approach to biological heart valve replacement. In the present study, we analyzed a new concept to process allogenic acellular matrix scaffolds of pulmonary heart valves after in vitro seeding with the use of autologous cells in a sheep model. METHODS AND RESULTS: Allogenic heart valve conduits were acellularized by a 48-hour trypsin/EDTA incubation to extract endothelial cells and myofibroblasts. The acellularization procedure resulted in an almost complete removal of cells. After that procedure, a static reseeding of the upper surface of the valve was performed sequentially with autologous myofibroblasts for 6 days and endothelial cells for 2 days, resulting in a patchy cellular restitution on the valve surface. The in vivo function was tested in a sheep model of orthotopic pulmonary valve conduit transplantation. Three of 4 unseeded control valves and 5 of 6 tissue-engineered valves showed normal function up to 3 months. Unseeded allogenic acellular control valves showed partial degeneration (2 of 4 valves) and no interstitial valve tissue reconstitution. Tissue-engineered valves showed complete histological restitution of valve tissue and confluent endothelial surface coverage in all cases. Immunohistological analysis revealed cellular reconstitution of endothelial cells (von Willebrand factor), myofibroblasts (alpha-actin), and matrix synthesis (procollagen I). There were histological signs of inflammatory reactions to subvalvar muscle leading to calcifications, but these were not found in valve and pulmonary artery tissue. CONCLUSIONS: The in vitro tissue-engineering approach using acellular matrix conduits leads to the in vivo reconstitution of viable heart valve tissue.

Animals↗
PubMed2000

Engineering of human vascular aortic tissue based on a xenogeneic starter matrix.

BACKGROUND: The goal for tissue engineering of vascular grafts is the replacement of a diseased vessel with a functional and stable graft. We now introduce a new concept for the tissue engineering of vessels. The idea was to humanize a previously acellularized, but structurally intact, xenogeneic vessel by repopulation with human autologous cells. To this purpose, a gentle nondenaturing and nondeterging acellularization procedure for xenogeneic aortas was developed. This structure was reseeded with pre-expanded peripheral vascular endothelial cells (EC) and myofibroblasts using specifically designed bioreactors. METHODS: Aortas from 15-30 kg female landrace pigs were acelullarized with a 0.1% trypsin solution for between 24 and 96 hr. Human vascular cells were harvested from saphenous vein biopsy specimens. Acellularized vessels were reseeded with EC and myofibroblasts. Cell viability after reseeding was assayed by fluorescence staining. Morphologic features of the acellularized matrix and tissue engineered vessel was assayed by transmission and scanning electron microscopy and histologic analysis. Nitric oxide-synthetase activity was investigated by mass spectrometric analysis of bioreactor supernatants. The in vivo immune response was tested by subcutaneous implantation of acellularized porcine aortic tissue in a rat model. RESULTS: The acellularization procedure resulted in an almost complete removal of the original resident cells, and the 3-D matrix was loosened at interfibrillar zones. However, the 3-D arrangement of the matrix fibers was grossly maintained. The 3-D matrix was covered with a fully confluent human endothelial cell layer obtained by continuous stress challenge in the bioreactor. Myofibroblasts migrated into positions formerly occupied by the xenogeneic cells. Nitric oxide synthetase activity was maintained in the bioartificial graft. T-lymphocyte and CD18 positive leukocyte infiltrate were greatly reduced after acellularization of porcine aortic specimens after implantation in the rat. CONCLUSIONS: Porcine vessels were acellularized and consecutively fully repopulated with human EC and myofibroblasts. This approach may eventually lead to the engineering of vessels immunologically acceptable to the host using a relatively short preparation period of 2-3 weeks. We expect matrix turnover in vivo leading to a gradual assimilation of the matrix structure by the host mediated by the hosts autologous cells.

Animals↗
PubMed2000

[Extended liver resection in small children under circulatory arrest and "low-flow" cardiopulmonary bypass].

In order to perform resections of tumors at critical sites in the liver in young children, liver resections in cardiac arrest and deep hypothermia under cardiopulmonary bypass have been developed. We report our experience with liver resection under cardiopulmonary bypass in three children with hepatoblastoma. In the first child the operation was performed under cardiac arrest and, the other two children were operated on under "low flow" conditions. The periods under cardiopulmonary bypass circulation were well tolerated. Extended right liver resections with vascular reconstructions were performed. The postoperative increase of liver enzymes was moderate. The increase in GOT was between 100 and 200 U/l. In spite of the extended tumor growth, reasonable long-term results were achieved by resection in combination with chemotherapy. One child has been living 8 years and another 10 months without tumor recurrence. The third child died due to sepsis during adjuvant chemotherapy, after she had recovered well from liver resection.

Age Factors↗