Biomedical subjects
M Kirsch
Publications and source records attributed to M Kirsch.
Therapeutic anti-angiogenesis for malignant brain tumors.
Malignant brain tumors, especially malignant gliomas, have a poor prognosis, a fact which has remained unchanged over the last decades despite the employment of multimodal therapeutic approaches. Malignant gliomas are among the most vascularized tumors known and the amount of vascularization has been correlated to their prognosis. Since tumor growth is dependent on concomitant vascularization, recent experimental studies have focused on the use of anti-angiogenic molecules as a novel strategy in brain tumor therapy. Angiogenesis inhibitors target at proliferating endothelial cells and suppress the formation of a sufficient vascular bed. Inhibitors such as TNP-470, suramin and angiostatin have shown their therapeutic potential in experimental studies. In a clinical setting, they could be applied for the treatment of multiple tumors or postsurgically as an adjuvant therapy to prevent recurrence. This article discusses presently available anti-angiogenic agents, emphasizing on substances already in clinical trials.
Silzone-coated St. Jude medical valve: a safe valve.
Careful follow up studies in patients receiving a Silzone-coated St. Jude Medical valve (67 aortic valves, 36 mitral valves, nine double valves) did not support the fear of a high risk of perivalvular leak and embolism rate. Freedom from perivalvular risk at 12 and 24 months follow up was 98.5+/-1.5% and 100% for the aortic and mitral valves, respectively. Freedom from any thromboembolic event was 96.6+/-2.4% at 12 and 24 months follow up in the aortic group, and 97+/-3% at 12 and 24 months in the mitral group. The risk of bleeding (92.2+/-3.8% at 12 and 24 months in the aortic group; 85.5+/-6.0% in the mitral group) illustrated the risk of mechanical valve implantation in an elderly population.
[Long-term results of surgery for type A acute aortic dissection].
The cases of 160 patients (126 men, mean age 57.5 +/- 13.3 years) operated consecutively as an emergency for a Stanford type A dissection of the aorta between 1980 and 2000 were reviewed. The cumulative follow-up was 716.7 patient-years with an average follow-up of 4.51 +/- 5.6 patient-years. The risk factors for early postoperative mortality (up to 3 months), late mortality (> 3 months) and reoperation (cardiac and/or vascular) were determined by multivariate analysis. The hospital mortality was 27.5%. Older ages, obesity, previous cardiac surgery, preoperative shock, medullary, renal or mesenteric ischaemia were significant risk factors for early mortality. The probability of actuarial survival was 66.1 +/- 3.8%, 57.7 +/- 4.2%, 52.2 +/- 4.6% and 45.3 +/- 5.5% respectively at 1, 5, 10 and 15 years. Chronic obstructive airways disease and a more recent operation date were significant risk factors for late mortality. Thirty patients underwent 37 reoperations after an average of 5.7 +/- 4.5 years. The actuarial probability for no reoperation was 96.9 +/- 1.8%, 74.7 +/- 5.3%, 60.8 +/- 6.8% and 39.3 +/- 9.1% at 1, 5, 10 and 15 years respectively. The presence of severe preoperative aortic regurgitation was the only significant risk factor for reoperation. Type A acute dissection of the aorta continues to have a high early mortality and a significant incidence of late complications. Patients with severe aortic regurgitation before surgery are at high risk for reoperation and should probably have more radical aortic repair at the initial operation.
[Computer-assisted coronary surgery].
Routine totally endoscopic, beating heart, coronary surgery should be made possible by the use of computer enhanced surgical techniques. It includes a totally endoscopic mammary artery harvesting, a correct exposure and an adequate stabilization of the coronary artery at the anastomotic site, a perfect anastomosis of the mammary artery on the left anterior descending coronary artery using a microsurgical suture technique. This complex surgical protocol will be reached by a step by step approach. The first 20 patients who accepted to be operated with tele-manipulated instruments make the substance of this first report. In 19 cases, the dissection of the internal mammary artery could be performed with an optimal result: the lack of bleeding during the dissection emphasizes the excellent visualization of the operative field and the precision of the dissection. The satisfactory blood flow in the mammary artery at the time of the coronary anastomosis suggests the lack of spasm and confirms the atraumatic dissection. The distal anastomosis of the coronary bypass has been performed through a mid line sternotomy to avoid an excessive prolongation of the operative time. The anatomic conditions and the quality of the vessel wall allowed to perform the coronary anastomosis with the tele-manipulated instruments in nine cases only: in six patients, the mammary artery has been implanted on the descending artery, in three, a venous autograft on the diagonal branch. Our initial clinical experience with this new technique suggests that a very precise and fine surgery can be performed with an acceptable prolongation of the operative time. More experience and further developments in the instrumentation are nevertheless required to allow completion of the entire procedure totally closed chest, on a beating heart.
Up-regulated CNTF plays a protective role for retrograde degeneration in the axotomized rat retina.
Using reverse transcription-polymerase chain reaction and in situ hybridization, we investigated the expression and cellular localization of ciliary neurotrophic factor receptor alpha (CNTFRalpha) in the rat retina following optic nerve transection (ONT). Following ONT, a signal for CNTFRalpha mRNA appeared in a layer-specific and time-dependent manner. In the ganglion cell layer, the signal showed a peak value 1 day after ONT, and then gradually decreased. In the inner nuclear layer the signal reached a peak value at 14 days of about 500% of control level, but then decreased at 4 weeks. Our findings suggest that CNTF might play a protective role for the retrograde degeneration of retinal cells induced by ganglion cell death in the rat retina following ONT.
[Circulatory assistance while waiting for heart transplantation. A report on the last 30 years].
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[Circulatory assistance while waiting for heart transplantation. Patient selection and choice of the assist system].
TWO CLINICAL SITUATIONS: Mechanical circulatory assistance can be indicated in two clinical situations: i) patients on the waiting list for heart transplantation who have chronic heart failure unresponsive to drug therapy and whose clinical status worsens; ii) patients with acute heart failure. INDICATIONS: The exact indications for mechanical circulatory assistance are difficult to establish. Hemodynamic criteria are no longer sufficient. Circulatory assistance may be proposed for chronic heart failure patients with a high risk of death or in a situation of acute deterioration. Among these patients, several risk factors can be used to establish scores that have a better predictive value than risk factors taken alone. Two predictive models have been recently established. The first one takes into account 7 independent variables: etiology, heart rate at rest, left ventricle ejection fraction, mean blood pressure, intraventricular rhythm disorder, VO2max and serum sodium). In addition to these variables, the second model also includes pulmonary wedge pressure. In selected patients with acute heart failure, circulatory assistance is needed as early as possible to avoid irreversible multiple organ failure. The crucial problem is rapid assessment of the feasibility of heart transplantation. PREOPERATIVE MORTALITY RISK FACTORS: Several variables can be used to predict survival in candidates for mechanical circulatory assistance on the heart transplantation waiting list. They include hemodynamic criteria, renal function, liver function, preoperative infection and the emergency nature of the need for circulatory assistance. CHOICE OF THE ASSIST SYSTEM: The choice depends both on the patient (surface area is important) and the underlying disease.
[Circulatory assistance while waiting for heart transplantation. Clinical course].
OUTCOME: In most cases, mechanical circulatory assistance prior to transplantation can restore the main vital functions allowing a progressive physical rehabilitation during the period of assistance. According to several international registries, the transplantation rate ranges from 62% to 69% and the proportion of transplanted patients who had circulatory assistance and who were discharged ranges from 65% to 69%. COMPLICATIONS: Bleeding (42.5%), right heart failure (20-25%), air embolism and multiple organ failure are the main causes of early morbidity and mortality. Infection (28.5%), thromboembolic events and technical failures are the most frequent late complications. DURATION OF CIRCULATORY ASSISTANCE: The optimal time for transplantation is the moment when the incidence of complications and technical problems for transplantation are at their minima while the patient's vital functions are at their maxima.
[Circulatory assistance while waiting for heart transplantation. Outcome of heart transplantation after mechanical circulatory assistance].
SURVIVAL: In most of the published (uncontrolled) studies, survival after transplantation is similar for patients who required mechanical circulatory assistance and those who did not. Two controlled studies have reported a better survival rate in patients who had preoperative circulatory assistance. COMPLICATIONS: Infections are more frequent in transplanted patients who had a period of circulatory assistance preoperatively than in those who were transplanted after medical treatment. The effect of circulatory assistance on heart graft rejection is debated. The same is true for coronary grafts.
Upregulation of ciliary neurotrophic factor in reactive Müller cells in the rat retina following optic nerve transection.
We have investigated the expression and cellular localization of ciliary neurotrophic factor (CNTF) in the rat retina following optic nerve transection. In the normal retina, CNTF immunoreactivity was restricted to profiles in the ganglion cell layer. Following optic nerve transection, immunoreactivity appeared in Müller cell somata and processes and its intensity increased between three and seven days post-lesion. Quantitative evaluation by immunoblotting confirmed that CNTF expression increased continuously up to 7 days after optic nerve transection (to 430% of control levels), but decreased again to 250% of controls at 4 weeks post-lesion. Our findings suggest that CNTF supplied by Müller cells may play a protective role for axotomized ganglion cells in the rat retina.
Ascorbate is a potent antioxidant against peroxynitrite-induced oxidation reactions. Evidence that ascorbate acts by re-reducing substrate radicals produced by peroxynitrite.
Peroxynitrite (ONOO(((-)))/ONOOH) is expected in vivo to react predominantly with CO(2), thereby yielding NO(2)(.) and CO(3) radicals. We studied the inhibitory effects of ascorbate on both NADH and dihydrorhodamine 123 (DHR) oxidation by peroxynitrite generated in situ from 3-morpholinosydnonimine N-ethylcarbamide (SIN-1). SIN-1 (150 micrometer)-mediated oxidation of NADH (200 micrometer) was half-maximally inhibited by low ascorbate concentrations (61-75 micrometer), both in the absence and presence of CO(2). Control experiments performed with thiols indicated both the very high antioxidative efficiency of ascorbate and that in the presence of CO(2) in situ-generated peroxynitrite exclusively oxidized NADH via the CO(3) radical. This fact is attributed to the formation of peroxynitrate (O(2)NOO(-)/O(2)NOOH) from reaction of NO(2)(.) with O(2), which is formed from reaction of CO(3) with NADH. SIN-1 (25 micrometer)-derived oxidation of DHR was half-maximally inhibited by surprisingly low ascorbate concentrations (6-7 micrometer), irrespective of the presence of CO(2). Control experiments performed with authentic peroxynitrite revealed that ascorbate was in regard to both thiols and selenocompounds much more effective to protect DHR. The present results demonstrate that ascorbate is highly effective to counteract the oxidizing properties of peroxynitrite in the absence and presence of CO(2) by both terminating CO(3)/HO( small middle dot) reactions and by its repair function. Ascorbate is therefore expected to act intracellulary as a major peroxynitrite antagonist. In addition, a novel, ascorbate-independent protection pathway exists: scavenging of NO(2)(.) by O(2) to yield O(2)NOO(-), which further decomposes into NO(2)(-) and O(2).
Acute brain death abolishes the cardioprotective effects of ischemic preconditioning in the rabbit.
BACKGROUND: Myocardial preconditioning with brief coronary artery occlusions before a sustained ischemic period is reported to reduce infarct size. We wished to evaluate whether ischemic preconditioning (IP) is efficient in an experimental brain death (BD) model in the rabbit. METHODS: Rabbits were randomized into four experimental groups of eight animals each. In the control group (CTRL), anaesthetized rabbits were subjected to 30 min of left coronary marginal branch occlusion and 90 min of reperfusion without any pretreatment. In the CTRL+IP group, anaesthetized rabbits were preconditioned with a 3-min ischemia and 3-min reperfusion sequence before coronary occlusion. In the BD group, rabbits were subjected to 90 min of BD before 30 min of coronary occlusion and 90 min of reperfusion. In the BD+IP group, BD rabbits were preconditioned as in the CTRL+IP group before coronary occlusion. BD was induced by rapid inflation of an intracranial balloon and was validated by clinical and electroencephalographic examinations. At the termination of the experiment, left ventricular volume (LVV), myocardial volume at risk (VAR) and infarct volume (IV) were determined with methylene blue and tetrazolium staining and were measured using planimetry. RESULTS: LW was not significantly different among the four experimental groups (CTRL, 6.54+/-0.90 cm3; CTRL+IP, 5.92+/-0.60 cm3; BD, 5.87+/-0.81 cm3; BD+IP, 6.16+/-0.95 cm3; P=ns). Furthermore, myocardial VAR, expressed as a percentage of LVV, was not significantly different between groups (CTRL, 20.0+/-4.2%; CTRL+IP, 22.32+/-2.25%; BD, 21.38+/-3.36%; BD+IP, 21.64+/-3.39%; P=NS). IV, expressed as a percentage of VAR, was significantly reduced in the CTRL+IP group compared with the CTRL group (15.76+/-8.47% vs. 49.95+/-1.51%; P<0.0001). In contrast, there was no significant difference in IV, expressed as a percentage of VAR, between the BD and the BD+IP groups (50.0+/-1.52% vs. 49.72+/-1.58%; P=NS). CONCLUSION: The data indicate that the infarct-limiting effect of IP is lost in BD rabbits. Thus, the clinical potential of IP in the context of organ transplantation seems to be severely compromised.
Differential regulation of ciliary neurotrophic factor and its receptor in the rat hippocampus following transient global ischemia.
To investigate a potential role of ciliary neurotrophic factor (CNTF) in transient global ischemia, we have studied the postischemic regulatory changes in the expression of CNTF and its receptor, the ligand-binding alpha-subunit (CNTFRalpha). Immunoblot analysis demonstrated CNTF levels were slightly upregulated already during the first day after ischemia and then increased markedly by more than 10-fold until 2 weeks postischemia. Immunoreactivity for CNTF became detectable 1 day after ischemia and was localized in reactive astrocytes. The intensity of the immunolabeling was maximal in CA1 during the phase of neuronal cell death (days 3-7 postischemia) and in the deafferented inner molecular layer of the dentate gyrus. Upregulation of CNTF expression was less pronounced in CA3 and absent in the stratum lacunosum moleculare and the outer molecular layer of the dentate gyrus and thus did not simply correlate with astroliosis as represented by upregulation of glial fibrillary acidic protein (GFAP). As shown by in situ hybridization, expression of CNTFRalpha mRNA was restricted to neurons of the pyramidal cell and granule cell layers in control animals. Following ischemia, reactive astrocytes, identified by double labeling with antibodies to GFAP, transiently expressed CNTFRalpha mRNA with a maximum around postischemic day 3. This astrocytic response was most pronounced in CA1 and in the hilar part of CA3. These results show that CNTF and its receptor are differentially regulated in activated astrocytes of the postischemic hippocampus, indicating that they are involved in the regulation of astrocytic responses and the neuronal reorganizations occurring after an ischemic insult.
Increased expression of ciliary neurotrophic factor receptor alpha mRNA in the ischemic rat retina.
Using in situ hybridization, we investigated the expression of ciliary neurotrophic factor receptor ((CNTFRalpha) mRNA in the rat retina rendered ischemic by elevation of the intraocular pressure (IOP). The IOP was increased to 120 mmHg and maintained for 60 min. The rats were sacrificed on the day of reperfusion (DRP) 1, 3, 7, 14, and 28. In the normal retina, the signal for CNTFRalpha mRNA was present in retinal cells in the inner nuclear layer (INL) and in the ganglion cell layer (GCL). On DRP 1, numerous cells in the INL and GCL showed a CNTFRalpha mRNA signal. From DRP 3 onwards, CNTFRalpha mRNA appeared in photoreceptor cells located in the outer part of the outer nuclear layer. The signal in these cells increased up to DRP 14 and then decreased at DRP 28. Our findings suggest that cells expressing CNTFRalpha mRNA may resist the degenerative processes induced by ischemic insult in the rat retina.
Contrast-enhanced breath-hold three-dimensional magnetic resonance angiography in the evaluation of renal arteries: optimization of technique and pitfalls.
The authors describe the optimization of a contrast-enhanced, breath-held, three-dimensional magnetic resonance angiography (CE-BH-3DMRA) technique in the assessment of the renal arteries and compare its utility with conventional x-ray angiography (XRA). Signal optimization using specific pulse sequence parameters was based on the patient's circulatory conditions, injection rate, and pulse sequence timing. Fifty-one patients (27 M, 24 F; mean age 69.7 years) were evaluated with CE-BH-3DMRA and XRA. All patients had an MR angiogram 3 months either before or after XRA. A test bolus study was performed for accurate assessment of transit time in each patient. A total of 51 patients (115 vessels) were studied in which the sensitivity and specificity for all renal artery stenoses including the proximal and mid-renal arterial segments were 96% and 92%, respectively. In-stent stenosis could only be diagnosed by quantifying flow beyond the stent using an additional triggered phase contrast cine pulse sequence. A total of 11 accessory renal arteries were correctly identified. In addition, fibromuscular dysplasia in two patients and stents in three patients were correctly identified on MRA. J. Magn. Reson. Imaging 2000;12:912-923.
Colonoscopic polypectomy in chronic colitis.
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Pretreatment of brain dead rabbits with pinacidil before prolonged cold-storage with an extracellular solution alters aortic endothelial function.
OBJECTIVE: Endothelial injury occurs during heart transplantation and contributes to the development of cardiac allograft vasculopathy. We have evaluated in a brain death model in the rabbit whether pre-treatment with the potassium channel opener (PCO) pinacidil before prolonged hypothermic storage with an extracellular solution would improve vascular endothelial recovery. METHODS: Rabbits were randomized into 4 experimental groups (n = 8 per group). In the control group (CTRL), abdominal aortic rings were assessed immediately after 90 minutes of anesthesia. In the brain death group (BD), aortic rings were assessed immediately after 90 minutes of brain death. In the STH group, aortic rings taken from brain dead rabbits were stored for 24 hours at 4 degrees C with the extracellular preservation solution of St. Thomas Hospital (STH) before assessment. In the STH + PCO group, the potassium channel opener pinacidil, 1 mg/kg, was administered intravenously to brain dead rabbits 10 minutes before explantation. Aortic rings were then stored for 24 hours at 4 degrees C with the STH solution before evaluation. Brain death was induced by rapid inflation of a sub-durally placed balloon and validated by clinical and electroencephalographic data. Concentration-response curves to acetylcholine (ACH, 10(-9) to 10(-4) mol/liter) and nitroglycerin (NGL, 10(-9) to 10(-5) mol/liter) were constructed in phenylephrinepre-contracted rings. RESULTS: ACH evoked a similar concentration-dependent relaxation in the CTRL (E(max): 95.8 +/- 2.9%; EC(50): -6.86 +/- 0.13 log M) and BD groups (E(max): 90.8 +/- 3.8%; EC(50): -6.75 +/- 0.15 log M). The concentration-relaxation curve was shifted rightward in the STH group (E(max): 76.7 +/- 7.1%; EC(50): -6.75 +/- 0.16 log M) in comparison with the CTRL and BD groups, but there were no significant differences in either E(max) or EC(50) values. After pinacidil pre-treatment, there was a further significant shift to the right of the concentration-relaxation curve to ACH (E(max): 77.4 +/- 5.0%; EC(50): -6.14 +/- 0.19 log M, p < 0.05 vs CTRL, BD and STH). There were no significant differences between groups in the concentration-relaxation curves to NGL in endothelium-intact and endothelium-denuded vascular rings (either E(max) or EC(50)). CONCLUSION: Pre-treatment of brain dead rabbits with pinacidil before prolonged cold-storage with STH solution significantly impaired endothelium-dependent vasorelaxation in comparison to storage with STH solution. The role of PCO pre-treatment in the context of cardiac transplantation needs to be reconsidered.