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Biomedical subjects

M J Wilhelm

Publications and source records attributed to M J Wilhelm.

At least 19 recordsLinked to original sources
PubMed2004

The place of research and the role of academic surgeons in cardiac surgery.

The development of the discipline of cardiac surgery was, to a large extent, guided by the vision and research of its pioneers. On the basis of their efforts, all the different areas of cardiac surgery were able to evolve including coronary artery bypass grafting, heart valve surgery, surgery of the aorta, congenital heart surgery, surgery for rhythm disorders including the implantation of pacemakers and defibrillators, and surgical treatment of advanced heart failure (for example, heart transplantations and mechanical circulatory support). The continued existence of cardiac surgery and its role in medicine in general will depend, to a significant extent, on the future research activities of its protagonists. Cardiac surgeon-scientists will play a pivotal role since they combine clinical experience with scientific knowledge and intuition which make them able to direct research to topics which will matter in the future. However, research costs money, and state or national funds will be not sufficient to support research as much as is necessary. Funding from third parties such as industry will increasingly be required. Due to this, however, the cardiac surgeon-scientist faces various challenges such as the evaluation of his skill in acquiring funds, conflicts with current ethical standards, conflicts of interest when receiving money from industry, and, as a result of the tough competition in this field, the temptation to commit fraud. The head of a department of cardiac surgery holds an important function as his initiative is decisive for the development of visions for the future and for the employment of surgeon-scientists who pursue visionary research. It will take the combined efforts of surgeon-scientists and departmental heads not only to maintain but to extend the position of cardiac surgery in medicine and society even further.

Biomedical Research↗
PubMed2004

First experience with rapamycin-based immunosuppression to improve kidney function after heart transplantation.

UNLABELLED: This study was designed to gain initial experience with rapamycin in thoracic organ transplant recipients with severely compromised kidney function, i.e. to see whether and how kidney function will improve with a rapamycin-based immunosuppressive protocol. METHODS: Twelve heart transplant patients were included into the study (serum creatinine > 2.5 mg/dL), with an average time after transplantation of more than 4 years. The calcineurin inhibitor (cyclosporine A = 9, tacrolimus = 3) was reduced by 50 %, and rapamycin added to reach a target level of 8 - 12 ng/dL. Azathioprine was halted, corticosteroid treatment remained unchanged. RESULTS: After implementing the rapamycin-based immunosuppression kidney function improved in all patients within one week. Serum creatinine dropped from 3.1 +/- 0.6 mg/dL to 2.7 +/- 0.5 mg/dL ( p = 0.0004), creatinine clearance increased from 30.4 +/- 11 mL/min to 40.8 +/- 10.5 mL/min ( p = 0.003). This improvement continued until 3 months after the conversion ( p = 0.032). Thereafter, no statistically significant changes were noted up to 6 months posttransplant ( p = 0.41). Serum cyclosporine levels dropped from 180 +/- 40 ng/mL to 132 +/- 46 ng/mL on average ( p = 0.002). Side-effects occurred in 4 patients and were all related to a rapamycin level exceeding 12 ng/mL. CONCLUSIONS: We conclude that transplant patients with impaired kidney function will have an immediate benefit from partially replacing calcineurin inhibitors by rapamycin.

Aged↗
PubMed2002

Left ventricular assist stand-by for high-risk cardiac surgery.

BACKGROUND: Patients with severely impaired left-ventricular pump function who are eligible for heart transplantation increasingly undergo high-risk cardiac surgery due to the scarcity of donor organs. If these patients also qualify for long-term mechanical support, the latter can be used as back-up in case of postcardiotomy failure. METHODS: Since 1994, 36 patients (34 male, 2 female; mean age 51 +/- 7 years) underwent coronary bypass surgery/aneurysmectomy (n = 27), aortic valve replacement (n = 4), both (n = 1), or partial left ventriculectomy (n = 4) with a long-term mechanical assist device (Novacor, HeartMate, DeBakey) and were kept on stand-by with the device. Average left ventricular ejection fraction was 23 +/- 9 %, NYHA 2.9 +/- 0.5, and CCS 2.7 +/- 0.9. An intraaortic balloon pump was inserted prior to surgery in 13 patients. RESULTS: In 31 patients, high-risk surgery was performed, whereas 5 patients underwent immediate device placement as coronary revascularization was deemed impossible. 6 patients had postcardiotomy failure after coronary bypass surgery and were immediately provided with a long-term assist system. There were no significant differences in risk factors between the patient subsets. All conservatively operated patients survived and left the institution after 9.4 days and are currently at NYHA 1.5 +/- 0.5 or CCS 1.0 +/- 0, respectively. 6 of the 11 LVAD patients could be bridged to heart transplantation after 43 - 418 days, and 1 patient is still on support. CONCLUSION: High-risk conventional surgery with LVAD stand-by is feasible and seems to be a valuable alternative for heart-transplant candidates.

Female↗
PubMed2001

The impact of anti-endotoxin core antibodies on endotoxin and cytokine release and ventilation time after cardiac surgery.

OBJECTIVES: We hypothesized that a temporary cardiopulmonary bypass (CPB)-induced reduction of endotoxin antibody levels contributes to elevated endotoxin levels and the associated inflammatory consequences, with a significant influence on the postoperative ventilation time period. BACKGROUND: Cardiac surgery using CPB induces a systemic inflammatory response syndrome with an associated risk of increased postoperative morbidity and mortality. METHODS: A total of 100 consecutive patients undergoing elective coronary artery bypass graft surgery using CPB were prospectively investigated. Endotoxin core antibodies (immunoglobulin [Ig] M/IgG against lipid A and lipopolysaccharide), endotoxin, interleukin (IL)-1-beta, IL-6, IL-8 and tumor necrosis factor-alpha were measured serially from 24 h preoperatively until 72 h postoperatively. RESULTS: Eighty-five patients had no complications (group 1), whereas 15 patients required prolonged ventilation (group 2). In both groups, there was a decrease of all antibodies 5 min after CPB onset, compared with baseline values (p < 0.001), an increase of endotoxin and IL-8 peaking at 30 min postoperatively (p < 0.001) and an increase of IL-6 peaking 3 h postoperatively (p < 0.001). In group 2, preoperative antibody levels were lower (p < 0.01)--specifically, the decrease in IgM was significantly stronger and of longer duration (p < 0.002)--and levels of endotoxin (p < 0.001) and IL-8 (p < 0.001) were higher at 30 min postoperatively. CONCLUSIONS: We conclude that an CPB-associated temporary reduction of anti-endotoxin core antibody levels contributes to elevated endotoxin and IL-8 release. Furthermore, lower levels of IgM anti-endotoxin core antibodies were associated with a greater rise in endotoxin and IL-8, as well as prolonged respirator dependence.

Adult↗
PubMed2001

Improvements in early behavior of rat kidney allografts after treatment of the brain-dead donor.

OBJECTIVE: To improve the quality of organs from brain-dead donors by assessing the influence of alternative strategies on the early behavior of kidneys after transplantation into unmodified hosts. SUMMARY BACKGROUND DATA: Kidneys transplanted from living donors perform consistently better than those from cadaver sources. The authors have recently shown that donor brain death produces inflammatory changes in peripheral organs within hours, amplifies coincident ischemia-reperfusion injury, and accelerates acute and chronic rejection. Normalization of the graft by donor hormone treatment has hitherto been unsuccessful. METHODS: A standardized rat model of brain death was used. Experimental groups included recipients of allogeneic grafts from living and brain-dead donors (F344-->LEW). Donors were treated immediately after induction of brain death either with intravenous steroids, which block inflammatory cytokine release, or a soluble P-selectin glycoprotein ligand (sPSGL), which blocks initial selectin-mediated cellular adhesion. Kidney grafts were examined serially up to 10 days by morphology, immmunohistology, and reverse transcriptase-polymerase chain reaction. RESULTS: Overall survival of ummodified recipients of kidneys from brain-dead donors was significantly reduced versus living donors. Animals with organs from brain-dead donors that had received steroids or sPSGL survived significantly longer than those from untreated brain-dead donors. The intensity of ischemia-reperfusion injury and of acute rejection was reduced. Cellular infiltration and transcription of mRNA of representative proinflammatory mediators were diminished. CONCLUSIONS: Treatment of organ donors at the time of brain death markedly improves organ quality after kidney transplantation, upgrading it to that from a living donor.

Animals↗
PubMed2001

Prediction of clinical outcome after cardiac surgery: the role of cytokines, endotoxin, and anti-endotoxin core antibodies.

Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) can lead to a systemic inflammatory response syndrome with organ failure and increased morbidity and mortality. The mechanisms of these findings are still under discussion. We investigated whether anti-endotoxin core antibodies, endotoxin, and proinflammatory cytokines influence the clinical course after cardiac surgery. Seventy-eight patients undergoing CABG using CPB were investigated. Anti-endotoxin core antibodies, endotoxin, interleukin (IL)-6, IL-8, IL-1beta, and TNF-alpha were measured 24 h preoperatively and up to 72 h postoperatively. Patients with a postoperative mechanical ventilation time below 24 h (n = 65; Group A) were compared to patients with prolonged respirator therapy (>24 h; n = 13; Group B). Preoperative antibody levels were significantly lower in Group B (P < 0.001). In this group, antibody levels remained decreased during the observation period (P < 0.001). Endotoxin significantly increased 30' postoperatively in both groups (P < 0.002). The increase in Group B was 3-fold higher (P< 0.001). IL-8 increased postoperatively in both groups, peaking 3 h after surgery (P < 0.001). In Group B, the IL-8 release was significantly higher than in Group A (P < 0.001). IL-6 significantly increased in both groups, reaching its maximum 24 h postoperatively (P < 0.001). No differences between groups were observed. No significant changes of IL-1beta and TNF-alpha were observed. We conclude that anti-endotoxin core antibodies may be predictive of adverse outcome after cardiac surgery. The imbalance between antibodies and endotoxin results in an exaggerated increase in endotoxin and IL-8 with an impact on clinical outcome.

Aged↗
PubMed2000

Activation of the heart by donor brain death accelerates acute rejection after transplantation.

BACKGROUND: Donor brain death upregulates expression of inflammatory mediators in the heart. It is hypothesized that these nonspecific changes trigger and amplify acute rejection in unmodified recipients compared with hearts from normal living donors. We examined the inflammatory and immunological consequences of gradual-onset donor brain death on cardiac allografts after transplantation. METHODS AND RESULTS: Functioning hearts were engrafted from normotensive donors after 6 hours of ventilatory support. Hearts from brain-dead rats (Fisher, F344) were rejected significantly earlier (mean+/-SD, 9. 3+/-0.6 days) by their (Lewis) recipients than hearts from living donor controls (11.6+/-0.7 days, P=0.03). The inflammatory response of such organs was accelerated, with rapid expression of cytokines, chemokines, and adhesion molecules and brisk infiltration of associated leukocyte populations. Upregulation of major histocompatibility class II antigens increased organ immunogenicity. Acute rejection evolved in hearts from brain-dead donors more intensely and at a significantly faster rate than in controls. CONCLUSIONS: Donor brain death is deleterious to transplanted hearts. The resultant upregulation of inflammatory factors provokes host immune mechanisms and accelerates the acute rejection process in unmodified hosts.

Animals↗
PubMed2000

Activation of inflammatory mediators in rat renal isografts by donor brain death.

BACKGROUND: Brain death (BD) has been thought to influence the early course of transplanted organs by triggering a series of nonspecific inflammatory events that in turn may increase the kinetics and intensity of the immunological host responses. In this study early nonspecific, cellular, and molecular changes occurring in kidney isografts from BD donors are compared with those from normal anesthetized, ventilated controls. METHODS: After induction of brain death, the animals were mechanically ventilated for 6 hr before organ removal. Only rats with stable blood pressure (mean arterial pressure >80 mmHg) were included. Serum creatinines were measured daily. Representative grafts were harvested 6 hr after brain death and between 1 hr and 5 days after engraftment for morphology, immunohistology, and reverse transcriptase-polymerase chain reaction. The presence of serum cytokines was assessed by enzyme linked immunoabsorbant assay. RESULTS: Serum creatinine levels rose slightly in recipients from BD donors. Serum interleukin-1beta levels increased within 6 hr versus controls (P<0.05). mRNA levels of interleukin-1beta and macrophage inhibitory protein-1 in the kidneys were up-regulated transiently before engraftment (6 hr after BD) and 1 hr after revascularization (P<0.05). By immunohistology, numbers of infiltrating polymorphonuclear leukocytes peaked at 24 hr in parallel with intragraft induction of P- and E-selectin, complement, and other proinflammatory chemokines and cytokines. At 5 days, the isografts from BD donors were highly infiltrated by host leukocyte populations associated with intense up-regulation of their products. In contrast, those from control donors remained relatively normal through this initial follow-up period. CONCLUSIONS: The intense nonimmune inflammation produced in isografts after donor BD may represent the initial stages of a continuum between an initial nonspecific and later immune reactivity, when placed in the context of allotransplantation.

Animals↗
PubMed2000

A model of gradual onset brain death for transplant-associated studies in rats.

BACKGROUND: The relatively few studies that have examined the systemic events after brain death have primarily involved large animals. For more precise definition of the physiology of this central catastrophe and its influence on peripheral organs, we have established a reproduceable model of gradual onset brain death in rats. METHODS: The central injury is induced by graded inflation of a Fogarty catheter placed intracranially under EEG and blood pressure monitoring. The rats were mechanically ventilated for 6 hr before removal of their kidneys. Complications and mortality are discussed. RESULTS: The majority (83%) of the 100 experimental animals could be used as organ donors. After a transient period of autonomic storm, the mean arterial blood pressure remained consistently between 80-100 mmHg, not appreciably different from controls. Despite normotension, the transplanted kidneys from brain dead donors showed a significantly longer interval to regain uniform cortical color and turgor than kidneys from control animals. CONCLUSIONS: We describe a controlled model of gradual onset brain death in the rat in which normotension can be sustained for several hours before the kidneys are removed for transplantation. Despite stable donor blood pressure, ischemia of peripheral organs may explain in part the increased incidence of delayed graft function of cadaver kidneys compared with those from living donors. This model is suitable for transplant-related studies involving organs from donors with irreversible central injury.

Animals↗
PubMed2000

Transplant vasculopathy: a model for coronary artery disease?

Although transplant vasculopathy and native atherosclerosis are clinically and pathologically different entities, the pathogenesis of both diseases exhibits some common mechanisms. Both may be regarded as responses to injury within a broadened concept of the immune system. Alloantigens (e.g. on donor endothelial cells) or autoantigens (e.g. oxydized LDL cholesterol) are presented by antigen presenting cells to the T cells of the body's immune system. With the appropriate costimulatory signal, this signal pattern generates a differentiated T cell, B cell, and inflammatory cell response whereas without the second signal, the immune cells undergo apoptosis. In case of immune cell proliferation and differentiation, a coordinated pattern of cytokine release is initiated. Monocyte-derived macrophages are also involved in this process which culminates in rolling, sticking, and diapedesis through the coronary vascular endothelium and phenotype switch of medial smooth muscle cells mediated by generation of growth-promoting cytokines. Thus, viewed within a broadened paradigm of the immune system's role both disease entities may represent different vignettes of an integrated pathophysiological response to an endothelial injury.

Animals↗
PubMed2000

Accelerated rejection of renal allografts from brain-dead donors.

OBJECTIVE: To define the potential influences of donor brain death on organs used for transplantation. SUMMARY BACKGROUND DATA: Donor brain death causes prompt upregulation of inflammatory mediators on peripheral organs. It is hypothesized that this antigen-independent insult may influence the rate and intensity of host alloresponsiveness after engraftment. METHODS: The rates of survival of unmodified Lew recipients sustained by kidney allografts from brain-dead, normal anesthetized, and anesthetized ventilated F344 donors were compared. Brain death was induced by gradually increasing intracranial pressure under electroencephalographic control. Tracheotomized brain-dead animals and anesthetized controls were mechanically ventilated for 6 hours before transplant nephrectomy. The rate and intensity of the acute rejection event were examined by histology, immunohistology, and reverse transcriptase-polymerase chain reaction. RESULTS: Animals bearing kidneys from brain-dead donors died of renal failure secondary to acute rejection at a significantly faster rate than those from anesthetized living controls or anesthetized animals ventilated for 6 hours. Within 3 hours after placement and reperfusion of brain-dead donor grafts, significant neutrophil infiltration was observed, followed by increasing numbers of macrophages and T cells. mRNA of proinflammatory mediators detected in kidneys within 6 hours of brain death and upregulated even before transplantation increased thereafter and appeared to accelerate and amplify host alloresponsiveness, as manifested by the rapid expression of chemokines, cytokines, adhesion molecules, and major histocompatibility complex class II antigens in the engrafted organ. The process evolved in the controls less intensely and at a slower rate. CONCLUSIONS: Donor brain death is a significant risk factor for peripheral organs used for transplantation. The activated state of such organs appears to trigger host immune mechanisms that accelerate the process of acute rejection. The effects of this central injury may explain in part the less satisfactory performance of cadaver organs in human transplantation compared with those from living sources.

Animals↗
PubMed2000

A comparison of fixed and variable doses of cocaine in producing and augmenting tolerance to its effects on schedule-controlled behavior.

Twelve pigeons were trained to peck a key under a fixed-ratio 20-response schedule of food presentation. Acute effects of cocaine (03-10.0 mg/kg), determined by administering the drug once per week, revealed dose-dependent decreases in frequency of key pecking. The pigeons were then divided into six pairs, matched with respect to acute dose-response curves. One of each pair received one of five different doses before each daily session (variable-dosing condition) and the other received a fixed dose equal to the arithmetic average of the doses experienced by its pair mate (fixed-dosing condition). Following 50 days of exposure, subjects in the variable-dosing condition were then switched to the fixed-dosing condition. Dose-response functions were then determined in both groups by substituting doses for the fixed daily dose, once per week. Rate-decreasing effects were attenuated similarly in both groups of subjects, both at the end of the variable-dosing regimen and during subsequent fixed dosing. Next, an attempt was made to increase the degree of tolerance. Specifically, pigeons in the variable-dosing condition were exposed repeatedly to a range of doses in which the largest dose was 1/8 to 1/4 log unit larger than in the original variable-dosing phase. Pigeons in the fixed-dosing group were exposed daily to the largest dose that did not eliminate key pecking by the end of the initial repeated-dosing regimen. Dose effects were determined after at least 35 days of exposure. If the dose-response function had shifted to the right, the largest dose for the variable-dosing subjects was increased by 1/8 to 1/4 log unit and the smallest dose in the sequence was eliminated, and another period of variable dosing commenced. For the fixed-dosing subjects, if the curve had shifted to the right, the fixed dose was increased by 1/8 to 1/4 log unit and the process repeated. Only very modest shifts of the dose-response function to the right were observed, and in several cases curves shifted left after exposure to larger doses. Overall the results suggest that a variable-dosing regimen holds promise as a technique for investigating the development of tolerance to the effects of cocaine, and that the magnitude of tolerance cannot be increased to any great degree by increasing the dose or doses repeatedly experienced. Additionally, it appears that experience with relatively large doses of cocaine may limit the degree to which tolerance can be developed, or decrease the magnitude of tolerance previously observed.

Animals↗
PubMed2000

Molecular and cellular events associated with ischemia/reperfusion injury.

I/R is an important non-specific, antigen independent event, which significantly influences the outcome of transplanted organs. Increasing graft immunogenicity and host alloresponsiveness inflicts additional deleterious effects. Ischemia has also been associated with donor conditions such as brain death and the non-heart-beating donor. As an event surrounding organ procurement, preservation and revascularization occurring early in the transplant process, it initiates a cascade of molecular and cellular events which trigger the release of proinflammatory mediators and attraction of various cell types infiltrating the tissues. This inflammatory event influences both acute functional and structural changes in the organ which contributes to reduced graft survival. Eventually, attenuation of I/R by strategies targeting various mediators and cell populations at different levels of the inflammatory cascade may constitute a means to improve both short and long-term success of solid organ grafts.

Blood Platelets↗