Biomedical subjects
Publications and source records attributed to M Schilling.
In this report, we describe the preliminary results from a feasibility and safety study on the clinical use of CD34-positive cells cultured from mobilized peripheral blood. Separation and cell expansion were successfully performed, and the patients tolerated the infusions without problems and achieved engraftment.
OBJECTIVE: To determine if plasma levels of Interleukin-6 (IL-6) across the lifespan correlate with bone density or plasma osteocalcin. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-five healthy community-dwelling volunteers aged 25-74 years. Exclusion criteria were smoking use of medications known to affect bone metabolism (corticosteroids, heparin, thyroxine, thiazides, and anticonvulsants), and presence of chronic inflammatory disease. MEASUREMENTS: Bone density was measured by dual-energy X-ray absorptiometry at the femoral neck and lumbar spine. Plasma levels of IL-6 and osteocalcin were determined by ELISA and RIA, respectively. RESULTS: Plasma levels of IL-6 increased with advancing age (P < .0001) and correlated with postmenopausal status (P < .0001). No correlation was observed between plasma IL-6 level and bone mineral density at either the lumbar spine or femoral neck, and none was observed with plasma osteocalcin. CONCLUSIONS: The elevation of plasma IL-6 observed following menopause is consistent with the proposed importance of estrogen in the regulation of IL-6. These findings do not provide support for a role of IL-6 in determination of peak bone density or subsequent development of osteoporosis. However, it is possible that plasma levels of IL-6 differ from those in the bone microenvironment.
Simultaneous kidney-pancreas transplantation represents an established method for the treatment of the diabetic patient with advanced renal failure. Continuous improvements of the surgical technique and of the immunosuppressive protocols resulted in 1-year graft survivals of the pancreas and the kidney of 75% and 85%, respectively. Currently the preferred surgical procedure is represented by the bladder drainage technique with a side-to-side duodenocystostomy. An intensive immunosuppressive regimen consisting of antilymphocytic antibodies, cyclosporine, azathioprine and steroids is mandatory to prevent and to treat rejection episodes. Graft rejection usually affects both kidney and pancreas concurrently; however, rejection generally manifests itself more distinct in the kidney, where it can be recognized and diagnosed much easier than in the pancreas. Simultaneous kidney-pancreas transplantation ensures normoglycaemia without the addition of exogenous insulin. Thereby, a substantial improvement in the quality of life can be attained. Furthermore, the transplantation of the pancreas leads to a stabilization of the neuropathy with a tendency towards improvement and effectively prevents the development of diabetic nephropathy in the simultaneously transplanted kidney. But no clear advantage has been shown for other diabetic complications like proliferative retinopathy and nephropathy. Compared to the transplantation of a kidney alone, one has to take into consideration a modest increase in patient morbidity due to the additional transplantation of the pancreas and to the more pronounced immunosuppressive therapy.
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Short preservation times for lungs, are the main obstacle to exchange organs and increase the number of lung transplantations. In abdominal organ preservation UW solution has extended preservation times by including impermeable anions, adenosine and scavengers to prevent parenchymal cell swelling, to improve ATP regeneration and to inhibit reactive oxygen radicals. Metabolic changes in rabbit lungs, cold stored in UW-solution were compared with changes in rabbit livers and kidneys. Rabbit lungs swell during rewarming after a short storage period as opposed to livers and kidneys. They furthermore accumulate significantly more potassium while maintaining high ATP concentration throughout storage and reperfusion.
Experimental preservation time for pulsatile perfused dog kidneys was extended from three to five days by phospholipase A2 inhibition suggesting a pathomechanical role of products of phospholipolysis like thromboxane and leukotrienes in the development of acute graft failure after renal transplantation. We therefore investigated the effects of thromboxane- and leukotriene synthase inhibitors on postoperative renal transplant function in a model of pulsatile perfusion preservation as well as a cold storage preservation of dog kidneys. Addition of a thromboxane-synthase-inhibitor to the perfusion medium in pulsatile perfused kidneys and the combined application of a thromboxane-synthase-inhibitor and a leukotriene-synthase-inhibitor to the recipient of a cold storage preserved graft, improved graft function and reduced the incidence of delayed graft function as well as histopathological features of acute tubular necrosis.
1275 patients were evaluated for HIV-1 + 2 seroprevalence and its association with clinical symptoms of HIV infection. Of 667 apparently healthy subjects, 8.2% had anti-HIV-1 antibodies. In 465 patients with clinical signs of AIDS, 39.4% were seropositive. 143 patients with miscellaneous symptoms had positive predictive values for HIV infection between 67% (vaginal ulcerations) and 20% (profound pyogenic abscesses). The WHO definition for AIDS had a specificity of 78.3%, a sensitivity of 72.2% and a predictive value of 61.6%.
Xenogeneic transplantation of solid organs is limited due to hyperacute rejection. In concordant systems, the mechanisms of rejection can be studied due to cross-reactivity of mediators with anti-human monoclonal antibodies. The aim of this study was to obtain information about the kinetics of proinflammatory cytokines and production of soluble adhesion molecules in the acute phase of reperfusion, eight kidneys from rhesus monkeys were perfused ex-vivo with human blood (group B/0) for 1 hour in a closed system. Blood levels of IL-1b, IL-6, TNFalpha, soluble ICAM, and E-selectin were measured using an ELISA technique under steady-state conditions. Cytokine levels rose significantly within the 60-min interval (IL-1b, 6.1 +/- 2.6-161.1 +/- 98.5 pg/ml; IL-6, 30.2 +/- 7.7-274.2 +/- 75.8 pg/ml; TNFalpha, 544.2 +/- 363.6-1651.0 +/- 25.7 pg/ml; P < 0.05). Immediately after the beginning of reperfusion, soluble ICAM-1 and selectin levels were abnormally high and rose constantly throughout the observation period, reaching significance at 60 min. High levels of proinflammatory cytokines may lead to an induction of adhesion molecules, thus, upregulating the leukocyte-endothelial interaction in a complement-independent mechanism. Specific pretreatment with monoclonal antibodies against ICAM-1, LFA-1, or other soluble mediators may be useful in down-regulating hyperacute rejection in trans-species transplantation.
Stem and progenitor cells from a variety of sources including bone marrow, cord blood, and peripheral blood have been used for transplantation. This study compares CD34 cells from all three sources. Flow cytometry analysis of CD34 cells in multiple samples of normal peripheral blood and patient peripheral blood mobilized with chemotherapy (cyclophosphamide/VP16), chemotherapy plus granulocyte colony stimulating factor (G-CSF), and G-CSF alone were compared to bone marrow and cord blood. Although the relative distribution of CD34 percentages in each preparation of cells varied widely, on average the percentage of CD34 cells in these different preparations was 0.15%, 0.6%, 2%, 0.45%, 1.68%, and 0.83% respectively. CD34 subset analysis was performed on these cell preparations using multicolor flow cytometry and antibodies to CD33, CD13, CD45RA, CD19, CD71, and CD38. The major differences observed were that bone marrow CD34 cells contain high percentages of CD19+ cells not found in significant quantity in the other cell preparations and cord blood CD34 cells contained a higher percentage of CD38-cells than the other cell preparations. A magnetic bead system was used with anti-CD34 antibody to purify CD34 cells from mobilized peripheral blood apheresis products, cord blood, and bone marrow. Efficient selection with high purities of CD34 cells was achieved with each of the cell preparations. Comparison of colony-forming activity of each of the cell preparations showed cord blood and mobilized peripheral blood to have slightly higher cloning efficiencies than bone marrow with higher numbers of erythroid blast-forming units (BFU-E) also observed in cord blood CD34 cells. Culture of isolated CD34 cells in liquid culture with interleukin-3, stem cell factor, G-CSF, and granulocyte-macrophage GM-CSF showed over a 100-fold expansion in cell numbers after 25 days, with the peak expansion of colony-forming cells occurring between days 11 and 16. Analysis of day-10 cells from these cultures showed them to be predominantly promyelocytes, myelocytes, and metamyelocytes, with cord blood CD34 cultures showing more promyelocytes than peripheral blood or bone marrow and bone marrow showing more metamyelocytes. Comparison of the proliferation of CD34 cells from these different cell preparations showed that cord blood CD34 cells cultured for 10 days averaged an 85-fold increase in cell numbers followed by mobilized peripheral blood CD34 cells, with an average 56-fold increase, and bone marrow CD34 cells, with an average 49-fold increase.
The growth and differentiation of selected bone marrow CD34+ cells stimulated with hematopoietic growth factors in lipid cultures were evaluated to determine whether cell types that may be useful for reducing the neutropenia associated with high-dose chemotherapy (HDC) can be produced and quantitated in vitro. CD34+ cells enriched from bone marrow were cultured for up to 5 weeks in interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) with or without stem cell factor (SCF) (also termed c-kit ligand). The mixture of IL-3, GM-CSF and G-CSF resulted in an 18-fold increase in cells after 10 to 12 days of culture and a 94-fold increase after 21 days. A 3-fold increase in colony-forming unit granulocyte-macrophage (CFU-GM) was observed after 10 days of culture. The addition of SCF during the first 10 days of culture further augmented the proliferation of cell numbers to 24-fold and colony-forming cells (CFC) to 8-fold after 10 days while cell numbers increased 130-fold after 21 days. Two-color flow cytometry defined phenotypes expressing CD11b and CD15 that represented maturation stages of neutrophils. Maturation of neutrophils in these cultures could be followed by the initial appearance after 3 to 7 days of a CD15+CD11b- phenotype representing promyelocytes, which gave rise after 2 to 3 weeks to a CD15+CD11b+ phenotype representing more mature neutrophil forms (metamyelocytes to segmented neutrophils). In contrast to normal neutrophil development, only a small fraction (10 to 15%) of the culture-derived neutrophils expressed CD16. These data define the kinetics and differentiation of neutrophils and neutrophil precursors from selected CD34+ cells in liquid cultures.
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The risks associated with transfusion can be minimized with autologous blood. The efficiency of preoperative deposit, preoperative hemodilution and intra- and postoperative autotransfusion in reducing homologous transfusions has been demonstrated. There seem to be few studies, however, that compared the different methods of autologous transfusion. This study was designed to evaluate the comparative efficiency of these methods. PATIENTS AND METHODS. Sixty-four patients scheduled for total hip arthroplasty were randomly divided into four groups: group I--preoperative autologous deposit: group II--preoperative hemodilution; group III--intra- and postoperative autotransfusion; group IV--control. Preoperative autologous donations were stored in CPDA-1 buffer. Three units of 450 ml were requested. A predonation hemoglobin (Hb) concentration of 11 g dl was required. Surgery was carried out in the 5th week after the first donation. Preoperative hemodilution to Hb 9 g/dl was carried out after induction of anesthesia and initial circulatory stabilization. A cell separator was used for intra- and postoperative autotransfusion. Postoperative autotransfusion of drainage blood was continued until 6 h after the beginning of the operation. Polygeline was used for volume resuscitation. If the Hb concentration fell below 9 g/dl in the operating room and intensive care unit or below 10 g/dl in the general ward, autologous blood or homologous packed red cells were transfused. Autologous blood collected with the cell separator was retransfused at the end of the operation and after the autotransfusion period irrespective of the actual Hb concentration. RESULTS. The general data of the patients, blood loss, and Hb concentration at the beginning of the study and postoperatively were comparable in the four groups. Homologous transfusion requirements amounted to 0 (0-1250) ml (median, range) packed red cells in group I (preoperative deposit). 500 (0-2000) ml in group II (hemodilution), 125 (0-1000) ml in group III (autotransfusion) and to 500 (0-1500) ml in group IV (control). In group I 14 of 16 patients, in group II 1 of 16, in group III 8 of 16 patients, in group IV 5 of 15 patients did not require homologous transfusion. The difference between group I and IV was significant (p = 0.004 and p = 0.003). Global coagulation tests, antithrombin III, and total serum protein were comparable in the four groups. DISCUSSION. The efficiency of preoperative hemodilution to reduce homologous transfusion requirements is limited]. In the present study, as in two other recent studies, hemodilution did not reduce homologous transfusion requirements. Autotransfusion with a cell separator can save approximately 50% of the erythrocytes lost during hip arthroplasty and 70% of the drainage loss. The homologous transfusion requirements for the autotransfused group reported here were less than in the control group; the difference, however, was not statistically significant. Patients participating in preoperative autologous deposit did not require homologous blood for hip arthroplasty in 62%-70% of cases in other investigations; in the present study 88% of the patients did not require homologous blood. CONCLUSION. Under the conditions studied, preoperative autologous deposit was the most efficient method of autologous transfusion for hip arthroplasty. It should be employed primarily.