Biomedical subjects
Publications and source records attributed to M Brandt.
An efficient strategy for the synthesis of a tetrapeptidyl substrate combinatorial array directed toward the caspases is described. Testing of this array with caspases 1 and 4 gave substrate hydrolytic profiles characteristic of each caspase, and permitted the identification of efficiently processed substrates. A comparison of this approach to that using a positional scanning library is presented.
BACKGROUND: In a prospective clinical trial, a group of patients receiving less invasive surgical procedure, including minithoracotomy in combination with cardiopulmonary bypass (group 1), was compared to a group of patients receiving conventional bypass surgery (group 2) for the treatment of coronary artery disease. METHODS: Group 1 included 85 patients (71 men, 14 women, aged 39 to 82 years, median 61.1 +/- 9.0 years); group 2 included 53 patients (38 men, 15 women, aged 51 to 79 years, median 62.0 +/- 6.1 years). RESULTS: There were no perioperative deaths in the whole series of patients. Time of operation was 256 +/- 43 minutes in group 1 and 150.0 +/- 53.6 minutes in group 2. Hospitalization was 6.0 +/- 1.4 days and intensive care unit stay 1 day for both groups. Back pain assessment on postoperative day 3 showed less pain in group 1. Three-month follow-up revealed ischemia in stress electrocardiogram in 2 patients (2.5%) in group 1 and in 2 patients (4.1%) in group 2. Coronary angiograms confirmed the stress-electrocardiogram findings. CONCLUSIONS: Surgical results are equal for both techniques. Even though time of operation is longer in patients receiving less invasive procedures, intensive care unit stay and hospital stays are the same length. Early postoperative back pain is less in group 1 and combined with faster convalescence.
We have followed up for a period of seven to nine years 100 consecutive arthroplasties of the hip in which an entirely HA-coated implant had been used. The clinical results were excellent and bony incorporation was extensive in all components. No stem became loose or subsided but five cups were revised because of loosening after 3.8 to 5.5 years, having functioned painlessly and shown radiological ingrowth. Revision procedures because of excessive polyethylene wear have been performed on 18 hips and are planned for six more. Two eroded metal backings with worn-through polyethylene were exchanged; six hips showed metallosis without polyethylene wear-through. There were two cases of granulomatous cysts in the groin and 66 hips had osteolysis located periarticularly, in the greater trochanter or in the acetabulum.
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To get some insight on the in vitro effect of TSH on the expression of two thyroid specific antigens (thyroglobulin (Tg) and thyroid peroxidase (TPO)) on the cell surface of cultured human thyroid cells an indirect immunofluorescence-activated cell sorter (FACStar IV, Becton-Dickinson) was used. Only half of the cultures responded to TSH by increased surface expression of the thyroid specific antigen Tg. In these cells, TSH stimulation of TPO expression showed a difference in epitopes recognized by murine monoclonal antibodies. Epitopes of domain D, recognized by monoclonal antibody 1, 30, 40 and 53 which are not involved in autoimmunity, were unaffected by TSH stimulation, (n = 2-10). In contrast, TSH regulated the surface expression of the TPO epitopes recognized by monoclonal antibody 15, 18, 24 and 60, which are known to be related to the serum autoantibody binding domain of TPO, (n = 6-8; p < 0.05). This indicated that increased activity of the thyroid cells selectively stimulated the expression of autoantigenic epitopes on the cell surface and supports the concept that increased cellular activity might predispose to the autoimmune processes leading to autoimmune thyroid disease.
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OBJECTIVES: In order to evaluate the benefit provided through less invasive surgical techniques for the treatment of multivessel coronary artery disease, a prospective clinical trial was started. METHODS: Group 1 included 53 patients (38 males, 15 females, age 51-79 years, mean 62.8 +/- 6.1 years) receiving conventional bypass surgery, group 2 included 69 patients (59 male, 10 female, age 43-82 years, mean 61.9 +/- 8.6 years) receiving less invasive surgical procedure including minithoracotomy in combination with cardiopulmonary bypass. RESULTS: No perioperative death occurred in the whole series of patients. Time of operation was 267 +/- 61 min in group 2 and 162.9 +/- 53.6 min in group 1. Intensive Care Unit stay was 1 day for both groups and Hospitalization 6.9 +/- 6.0 for group 1 and 7.5 +/- 2.6 days for group 2. Perioperative bleeding was less in group 2 (P > 0.01). Back and chest pain assessment on postoperative day 3 showed less pain in group 2 (P < 0.05). Three-month follow-up revealed ischemia in stress electrocardiogram in two patients (3.8%) in group 1 and in 2 patients (2.9%) in group 2. Coronary angiograms confirmed the stress ECG findings. There was one (1.4%) redo operation in group 2 and two (3.8%) in group 1. CONCLUSIONS: Both techniques are equal efficient. Even though time of operation is longer in patients receiving less invasive procedure, intensive care unit stay and hospitalization is exactly as long. Patients receiving minimally invasive surgery bleed less and have less pain early postoperatively.
BACKGROUND: If coronary artery multivessel disease is the target of a minimally invasive procedure, either median sternotomy or cardiopulmonary bypass can be avoided. METHODS: We used an alternate technique instead of minithoracotomy and cardiopulmonary bypass to treat 102 patients (82 men, 20 women; age range, 39 to 82 years; median, 61.0 +/- 8.9 years) for coronary artery single-vessel, double-vessel, or multivessel disease between November 1996 and January 1998. Twenty-nine patients (22 men, 7 women; age range, 46 to 78 years; median, 69.0 +/- 8.4 years), who were in a high-risk group for the development of perioperative complications because of the use of cardiopulmonary bypass, received median sternotomy and a beating heart procedure using the Octopus stabilizing technique. The left anterior descending coronary artery was the target vessel in all patients except for 1, in whom the left internal mammary artery was used. RESULTS: There was no intraoperative death in either series. In the beating heart group (Octopus) 2 patients died on postoperative day 31 and 35, respectively, of postoperative pneumonia. CONCLUSIONS: Both techniques present safe alternative procedures to conventional coronary artery bypass grafting in patients with coronary artery multivessel disease.
OBJECTIVE: The treatment of coronary single vessel disease under minimally invasive surgical conditions was followed by the treatment of coronary multivessel disease using a new technique. METHODS: Using this technique 100 patients (80 male, 20 female, median age 61.0+/-8.9 years, ranged from 39 to 82 years) with coronary single vessel disease, double vessel disease or multivessel disease were treated between November 1996 and December 1997. Via a small (6-9 cm) left lateral chest incision in the second or third intercostal space, the left internal thoracic mammary artery (LIMA) was harvested and access to the central portion of the heart including the ascending aorta was obtained. In parallel, saphenous vein segments were harvested. Arterial cannulation was instituted via the ascending aorta, thus avoiding retrograde flow. In all patients except three the LIMA was used for the left anterior descending artery (LAD). In addition vein grafts were used for revascularization of the other coronary arteries. All cardiac anastomoses were performed during cardioplegic arrest after external aortic cross clamping and antegrade application of cardioplegia. RESULTS: No death or intraoperative complications were observed in this series. The median hospital stay was 6.0+/-1.4 days (median+/-SEM). Postoperative complications were reexplored for bleeding (n = 1), delayed wound healing (n = 2), wound infections (n = 4), lymphatic fistulas (n = 4), and a chest wall hernia (n = 1). CONCLUSIONS: This minimally invasive surgical technique presents a safe alternative to conventional coronary artery surgery avoiding sternotomy related complications and decreasing hospital stay and morbidity.
Experimental preconditioning is commonly regarded as a powerful protective phenomenon in case of subsequent ischemia. However, little is known about the applicability of preconditioning as an adjunct to cardioplegic myocardial protection in routine coronary surgery. For this reason, a prospective clinical study (611995 to 4/1996) was initiated to evaluate normothermic ischemic preconditioning prior to crystalloid or cold blood cardioplegic arrest. Preconditioning was performed in two cycles of 5 min ischemia and 10 min reperfusion. Four groups of 7 patients each were compared regarding release of troponin T, creatine kinase-myocardial isoform (CK-MB), lactate, and total CK in coronary sinus effluents over a 12-hour period. In the absence of perioperative myocardial infarction, there were no significant differences in these ischemic and metabolic parameters. Unexpectedly, the heed of postoperative pharmacological inotropic support was greater after preconditioning. These results may indicate that ischemic preconditioning as an adjunct to cardioplegic arrest may be associated with impairment of left-ventricular contractility, thus even exerting potentially detrimental functional effects. Overall, the proven beneficial effects of experimental preconditioning seem not to be directly transferable into the clinical settings.
During allograft rejection, leukocyte infiltration in the graft is regulated by various adhesion molecules. Treatment with monoclonal antibodies to ICAM-1 and LFA-1 (CD11 a) induces specific tolerance after murine heart transplantation. In this study, we investigated the possibility of tolerance induction using these antibodies in a fully incompatible rat heart transplant model. Heterotopic, intra-abdominal heart transplantation was performed using Dark Agouti (DA) rats as donors and Lewis (LEW) rats as recipients. Group A (n = 6) received no immunosuppression and served as controls. In group B (n = 6) 500 micrograms/kg per day 1A29 (anti-ICAM-1) was administered intravenously (i.v.) for 5 days; group C rats received the same dosage of WT.1 (anti-CD11 a) i.v. for 5 days. In group D (n = 6), rats received combined i.v. administration of anti-CD11 a and anti-ICAM-1 (500 micrograms/kg per day of each, for 5 days. The antibodies used were monoclonal mouse anti-rat antibodies produced from hybridomas. Allograft survival was monitored by daily palpation of the graft. There was no statistically significant difference in allograft survival between the groups (A: 5.7 +/- 0.5 days; B: 5.7 +/- 0.5 days; C: 5.7 +/- 0.5 days; D: 6.2 +/- 0.4 days). Treatment with monoclonal antibodies to ICAM-1 and LFA-1 alone or in combination had no effect on allograft survival after heart transplantation between fully incompatible rat strains. We conclude that induction of tolerance using these antibodies seems inconceivable in human heart transplantation.
BACKGROUND: The standard technique for orthotopic heart transplantation includes right and left atrial anastomoses, which potentially disturb the integrity of the donor atria. Consequently, electrophysiologic abnormalities such as atrial flutter and fibrillation may occur even late after heart transplanation. METHODS: Over a 3-year period, 39 heart transplantations were performed using a standard right atrial anastomosis (group A), and 40 were done using bicaval anastomoses (group B). In each group, data of 30 consecutive patients with a minimum follow-up of 9 months were reviewed retrospectively to assess the incidence of atrial arrhythmia after hospital discharge. RESULTS: Early postoperatively, there was no difference in the duration of temporary pacemaker requirement and incidence of permanent pacemaker implantation (group A, 7%; group B, 7%; not significant) between the two groups. In 12 patients in group A (40%), 16 episodes of atrial flutter and fibrillation were detected 20 to 205 days after heart transplantation. In group B, 1 patient (4%) suffered from atrial fibrillation on day 116 after the operation (p < 0.001). CONCLUSIONS: Preservation of the integrity of the right donor atrium by construction of bicaval anastomoses results in a significantly decreased incidence of atrial flutter and fibrillation after heart transplantation when compared with the standard technique.
OBJECTIVE: Adhesion molecules regulate the infiltration of leukocytes into the graft during rejection after lung transplantation. The first step of the adhesion cascade is mediated by selectins. Sialyl-LewisX is a ligand of P-selectin. The purpose of the study was to evaluate SLX, a synthetic oligosaccharide analog of Sialyl-LewisX, for anti-rejection prophylaxis after allogeneic and xenogeneic left lateral, orthotopic rat lung transplantation. METHODS: In groups A and B, allogeneic lung transplantation was performed using fully incompatible rat strains (donors: Dark-Agouti (RT1a); recipients: Lewis (RT11)). In group A (n = 10), recipients recieved 200 microg/d SLX i.v. on day 0-4. Group B rats (n = 10) served as untreated controls. The animals were sacrificed on days 5 and 10, respectively. In groups C and D, xenogenic lung transplantation was performed using Gold Syrian hamsters as donors and Lewis rats as recipients. In group C (n = 10), recipients received 200 microg/d SLX i.v. on day 0-4. Group D rats (n = 10) served as untreated controls. The animals were sacrificed on days 2 and 5, respectively. Rejection was graded by histology from 0 (no rejection) to 5 (necrosis). By immunhistology, alveolar, interstitial CD11a, CD18 and VLA-4 positive leukocytes were counted. RESULTS: Histologically, there were a lower grade of rejection (A: 2.7 +/- 0.6; B: 4.0 +/- 0.0; P < 0.05) and fewer CD11a positive leukocytes (A: 66 +/- 27; B: 186 +/- 73; P < 0.05) on day 5 in the SLX-treated allograft group compared to the untreated group. In xenotransplantation, SLX also reduced the grade of rejection (C: 3.3 +/- 0.5; D: 4.7 +/- 0.5; P < 0.05) and the number of CD11a positive leukocytes (C: 145 +/- 22; D: 176 +/- 20; P < 0.05) on day 2. CONCLUSIONS: It is concluded, that the administration of SLX significantly reduces allograft rejection. After discontinuation treatment with SLX unmodified rejection appeared. SLX also modifies xenograft rejection, but to a lesser extent, and xenograft necrosis appeared during treatment in this model.
OBJECTIVE: Encouraging results on myocardial preconditioning in experimental models of infarction, stunning or prolonged ischemia raise the question whether preconditioning techniques may enhance conventional cardioplegic protection used for routine coronary surgery. METHODS: A prospective clinical trial was conducted to investigate the effect of additional ischemic normothermic preconditioning prior to cardioplegic arrest applying cold blood cardioplegia in patients scheduled for routine coronary surgery (3 vessel disease, left ventricular ejection fraction > 50%). Two cross clamp periods of 5 min with the hearts beating in sinus rhythm were applied followed by 10 min of reperfusion, each (n = 7, group I). Inducing moderate hypothermia cold blood cardioplegia was delivered antegradely. In control groups, cold intermittent blood cardioplegia (n = 7, group II) was used alone. Coronary sinus effluents were analyzed for release of creatine kinase (CK), CK-MB, lactate, and troponin T at 1, 3, 6, 9, and 12 h. In addition, postoperative catecholamine requirements were monitored. RESULTS: The procedure was tolerated well, and no perioperative myocardial infarction in any of the groups studied occurred. Concentrations of lactate tended to be higher in group I, but this difference was not significant. In addition, no significant differences for concentrations of CK, CK-MB, and troponin T were found. Following ischemic preconditioning an increased dosage of dopamine was required within the first 12 h postoperatively (group I: 2.63 +/- 1.44 microg/kg/min, group II: 0.89 +/- 1.06 microg/kg/min). CONCLUSIONS: Combining ischemic preconditioning and cardioplegic protection with cold blood cardioplegia does not appear to ameliorate myocardial protection when compared to cardioplegic protection applying cold blood cardioplegia alone. Inversely, contractile function seemed to be impaired when applying this protocol of ischemic preconditioning.
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BACKGROUND: During rejection and reperfusion injury, infiltration of leukocytes into the lung allograft is regulated by adhesion molecules, especially selectins. Sialyl-Lewis X (SLX), an oligosaccharide, is a membrane ligand molecule of P-selectin adhesion receptors. In this study, we investigated the effect of intravenous administration of a synthetic oligosaccharide analog of SLX on rejection and reperfusion injury after rat lung transplantation. METHODS: Left lateral, orthotopic, allogeneic lung transplantation was performed between fully incompatible rat strains (Dark Agouti-->Lewis) after an average total ischemic time of 45 minutes. Group A (n = 6) served as control; no immunosuppression was used. In group B (n = 6), rats received 200 micrograms/kg/day SLX intravenously on days 0 to 4. The animals were killed on days 5 and 10, respectively. In groups C and D, syngeneic lung transplantation was performed (Lewis-->Lewis), with an ischemic time of 7 hours. Group C (n = 6) served as untreated controls. Group D rats (n = 6) received a single dose of 20 mg/kg SLX at the end of the ischemic time. The animals were killed on days 2 and 5, respectively. RESULTS: In group B rats, treated for rejection, a lower grade of rejection (2.7 +/- 0.6 vs 4.0 +/- 0.0, p < 0.05) and fewer infiltrating CD11a-positive leukocytes (6.6 +/- 2.7 vs 18.6 +/- 7.3, p < 0.05) were found histologically compared with group A. In group D rats, treated for reperfusion injury, a significant reduction of reperfusion injury was detected on chest radiograms and by histologic study. CONCLUSIONS: A synthetic oligosaccharide analog of SLX reduces allograft rejection and reperfusion injury by abrogation of P-selectin-dependent leukocyte-endothelial interaction. According to these findings, treatment with oligosaccharides to reduce reperfusion injury and rejection seems to be a promising strategy for clinical lung transplantation.
An in vitro system of secondary and tertiary cultures of human thyroid epithelial cells (TFECs) in monolayer is described. The function of the cells was evaluated by the second messenger cAMP and the end product thyroglobulin (Tg). The Tg production from the cells was measured in the supernatant by a newly developed enzyme-linked immunosorbent assay. The TFECs in secondary monolayer cultures had preserved the ability to produce Tg and cAMP despite lack of polarization. Furthermore, a preserved ability of TSH-stimulated production of Tg and cAMP in 12-week-old secondary and tertiary cultures was found. However, the Tg and cAMP levels decreased gradually with the age of the cultures. In the secondary culture the TSH-stimulated Tg production decreased from 253 ng/micrograms DNA (205-263) after 3 weeks to 18 ng/micrograms DNA (6-81), P < 0.001, n = 6 after 12 weeks and TSH-stimulated cAMP production from 660 pmol/micrograms DNA (500-840) to 60 (40-200), P < 0.001, n = 6. The decreased responsiveness of long-term cultures results in preference of short-term secondary cultures, which provide a more suitable experimental model for in vitro investigation of human thyroid cell functions.
An in vitro system of secondary cultures of human thyroid follicular epithelial cells in monolayer is described. The 72-h influence of serum and six supplements (thyrotropin, insulin, somatostatin, transferrin, hydrocortisone, glycyl-histidyl-lysine acetate) on growth and function in presence of 3-isobutyl-L-methyl-xanthine (IBMX) was investigated. The function of the cells was evaluated by production of the second messenger adenylate cyclase (cAMP) and the end product thyroglobulin (Tg). Growth was measured as the 3H-thymidine uptake of the cells. Three days of TSH-depletion preceeded the experiments. In presence of IBMX TSH stimulated cAMP production, while stimulation of Tg was only present in some cultures. In absence of IBMX TSH always stimulated the Tg production. The stimulation was independent of the presence of the other five investigated nutritional factors in physiological concentrations. TSH in concentrations from 0.1-10 U/1 stimulated the 72ih 3H-thymidine uptake of the cells. The TSH-stimulated production of Tg and cAMP decreased significantly with increasing concentrations of fetal calf serum (0-10%), (tau = 0.49, P < 0.001, n = 6-29 and tau = 0.75, P < 0.001, n = 6-29, respectively). Thus, serum as a complex, variable and not fully characterized mixture of hormones and growth factors was crucial to the attachment of the cells to the substrate, but inhibited differentiated functions of the human thyroid cells.