Traumatic tricuspid insufficiency after horse kick.
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Adult↗
Biomedical subjects
Stefan Fischer
Publications and source records attributed to Stefan Fischer.
Recipient T cells mediate reperfusion injury after lung transplantation in the rat.
Leukocytes have been implicated in ischemia-reperfusion (IR) injury of the lung, but the individual role of T cells has not been explored. Recent evidence in mice suggests that T cells may play a role in IR injury. Using a syngeneic (Lewis to Lewis) rat lung transplant model, we observed that recipient CD4(+) T cells infiltrated lung grafts within 1 h of reperfusion and up-regulated the expression of CD25 over the ensuing 12 h. Nude rats (rnu/rnu) and heterozygous rats (rnu/+) were used to determine the role of T cells in IR injury. No significant difference in lung function was observed between nude and heterozygous recipient rats after 2 h of reperfusion. However, after 12 h of reperfusion, recipient nude rats had significantly higher oxygenation and lower peak airway pressure than recipient heterozygous rats. This was associated with significantly lower levels of IFN-gamma in transplanted lung tissue of recipient nude rats. Reconstitution of recipient nude rats with T cells from heterozygous rats restored IR injury after 12 h of reperfusion. The effect of T cells was independent of neutrophil recruitment and activation in the transplanted lung. These results demonstrate that recipient T cells are activated and mediate IR injury during lung transplantation in rats.
Adoptive Transfer↗
How well does charge reparametrisation account for solvent screening in molecular mechanics calculations? The example of myosin.
The rate constant of an enzyme-catalysed reaction is one of the major target properties to understand protein function. Atomic-detail computer simulations can in principle be used to estimate rate constants from the energy profile along the reaction coordinate. For such simulations, molecular mechanics is combined with a quantum description of the reaction process. In molecular mechanics calculations, the electrostatic field is represented by the Coulomb potential of partial atomic charges which have been parametrised for small building blocks in vacuum and transferred to the macromolecule. In aqueous solution, however, the electrostatic interactions are affected by the solvent polarization. While this can be described by numerically solving the Poisson-Boltzmann equation, it is computationally expensive. A simple approximation to this is to optimally reproduce the electrostatic potential in solution by reparametrising the partial atomic charges in such a way that a simple Coulomb potential can still be used. Such a procedure would allow to perform fast calculations of reaction processes in proteins while accounting for the solvent screening effect. Here, this method is tested on myosin, a motor protein that is both an enzyme and exists in very different conformations.
Adenosine Triphosphate↗
Molecular dynamics simulation reveals a surface salt bridge forming a kinetic trap in unfolding of truncated Staphylococcal nuclease.
Surface salt bridges are ubiquitous in globular proteins. Their contribution to protein stability has been extensively debated in the past decade. Here, molecular dynamics simulations are performed starting from a non-equilibrium state of Staphylococcal nuclease (SNase) with C-terminal truncation (SNaseDelta). The results indicate a key role in the unfolding of the surface salt bridge between arginine 105 and glutamate 135. Experimentally, SNaseDelta is known to be partially unfolded. However, in simulations over 1 ns at 300 K and over 500 ps at 400 K, SNaseDelta remains stable in the native-like folded conformation, the salt bridge hindering unfolding. When the potential function is altered so as to selectively weaken the salt bridge, which then breaks rapidly at 430 K, the protein starts to unfold. The results suggest that breaking of this salt bridge presents a significant barrier to the unfolding transition of SNaseDelta from a native-like state to the unfolded state. Potential of mean force calculations indicate that the barrier height for this transition is approximately 7 kcal/mol.
Arginine↗
Anticoagulant therapy in pregnant women with mechanical heart valves.
Managing women with mechanical heart valves during pregnancy poses a particular challenge as there are no available controlled clinical trials to provide guidelines for effective antithrombotic therapy. Oral anticoagulation with coumadin-derivates administration is associated with coumarin embryopathy, and subcutaneous administration of unfractioned heparins (UFH) has been reported to be ineffective in preventing thromboembolic complications. Due to the increased risk of thromboembolic events when UFH is used, low molecular weight heparins (LMWH) were considered to be an alternative. The evidence in the literature regarding the long-term use of LMWH as the only anticoagulant after mechanical heart valve replacement is limited only to a few reports encompassing only 25 patients, with treatment failure in 20%. These data show that anticoagulation with LMWH only is neither safe nor effective in preventing thromboembolic events after mechanical heart valve replacement, in pregnant or non-pregnant women.
Anticoagulants↗
In vivo repopulation of xenogeneic and allogeneic acellular valve matrix conduits in the pulmonary circulation.
BACKGROUND: Approaches to in vivo repopulation of acellularized valve matrix constructs have been described recently. However, early calcification of acellularized matrices repopulated in vivo remains a major obstacle. We hypothesised that the matrix composition has a significant influence on the onset of early calcification. Therefore, we evaluated the calcification of acellularized allogenic ovine (AVMC) and xenogenic porcine (XVMC) valve matrix conduits in the pulmonary circulation in a sheep model. METHODS: Porcine (n = 3) and sheep (n = 3) pulmonary valve conduits were acellularized by trypsin/EDTA digestion and then implanted into healthy sheep in pulmonary valve position using extracorporeal bypass support. Transthoracic echocardiography (TTE) was performed at 12 and 24 weeks after the implantation. The animals were sacrificed at week 24 or earlier when severe calcification of the valve conduit became evident by TTE. The valves were examined histologically and biochemically. RESULTS: All AVMC revealed severe calcification after 12 weeks with focal endothelial cell clustering and no interstitial valve tissue reconstitution. In contrast, after 24 weeks XVMC indicated mild calcification on histologic examination (von Kossa staining) with histologic reconstitution of valve tissue and confluent endothelial surface coverage. Furthermore, immunohistologic analysis revealed reconstitution of surface endothelial cell monolayer (von Willebrand factor), and interstitial myofibroblasts (Vimentin/Desmin). CONCLUSIONS: Porcine acellularized XVMC are resistant to early calcification during in vivo reseeding. Furthermore, XVMC are repopulated in vivo with valve-specific cell types within 24 weeks resembling native valve tissue.
Animals↗
Methylene blue: the drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass?
OBJECTIVES: Vasoplegia is a frequent complication after cardiopulmonary bypass that often requires the application of norepinephrine. In a number of cases, however, vasoplegia is refractory to norepinephrine. The guanylate cyclase inhibitor methylene blue could be an attractive treatment alternative in such cases. This study examines the results of methylene blue therapy for norepinephrine-refractory vasoplegia after cardiopulmonary bypass. METHODS: A total of 54 patients with norepinephrine-refractory vasoplegia after cardiopulmonary bypass were treated with methylene blue (2 mg/kg) administered intravenously through a period of 20 minutes. The effects on hemodynamics, norepinephrine dosage, and clinical outcome were evaluated. RESULTS: Three patients (5.6%) died during the hospital stay. A clinically relevant increase in systemic vascular resistance and a decrease in norepinephrine dosage were observed in 51 patients within 1 hour after methylene blue infusion. Four patients (7.4%) had no response to methylene blue. No adverse effects related to methylene blue were observed. CONCLUSIONS: A single dose of methylene blue seems to be a potent approach to norepinephrine-refractory vasoplegia after cardiopulmonary bypass for most patients, with no obvious side effects. Guanylate cyclase inhibitors could be a novel class of agents for the treatment of norepinephrine-refractory vasoplegia after cardiopulmonary bypass. A controlled clinical trial is now needed to evaluate the role of methylene blue in this situation.
Cardiopulmonary Bypass↗
Interleukin 10 gene transfection of donor lungs ameliorates posttransplant cell death by a switch from cellular necrosis to apoptosis.
BACKGROUND: We have previously shown that cell death is a pathophysiologic consequence of ischemia-reperfusion and that interleukin-10 gene therapy improves the function of transplanted lungs. Interleukin-10 downregulates the inflammatory response and can inhibit apoptosis. The objective was to determine whether donor lung transfection with the interleukin-10 gene ameliorates lung dysfunction by decreasing cell death after transplantation. METHODS: Single lung transplants were performed in 3 groups of rats (n = 5 each): AdhIL-10, transtracheal administration of Ad5E1RSVhIL-10 (5 x 10(9) pfu); EV, empty vector; and VD, vector diluent (3% sucrose). After in vivo transfection, donor lungs were excised, stored at 4 degrees C for 24 hours, and then transplanted. After 2 hours of reperfusion, lungs were flushed with trypan blue and fixed. TUNEL staining was used for the detection of apoptosis. This combined staining technique allows one to determine the mode of cell death by distinguishing apoptotic dead cells from necrotic dead cells. RESULTS: Lung function was superior in the interleukin-10 group (P =.0001) vs the EV and VD group (Pao(2): 240 +/- 31 mm Hg vs 98 +/- 17 mm Hg vs 129 +/- 11 mm Hg, respectively). Although the total number of dead cells (as percent of total cells) was similar in all groups (32.7% +/- 3.2%, 30.2% +/- 2.5%, and 30.3% +/- 3.8%), interestingly, apoptosis was highest in interleukin-10 lungs (9.7 +/- 1.9 vs 2 +/- 1.9 and 1.8 +/- 2, P =.0001), and necrosis was lowest in the interleukin-10 group (20.6 +/- 5.7 vs 28.3 +/- 3.1 and 30.3 +/- 4.2, P =.01). CONCLUSIONS: AdhIL-10 gene transfection improves function of transplanted lungs. Although the total number of cells dying as a result of the transplant process did not change, the mode of cell death appears to have been modified. It is possible that AdhIL-10, by decreasing proinflammatory cytokine production, ameliorates the overall injury and preserves the ability of damaged cells to undergo a more quiescent and less tissue-damaging mode of cell death-apoptosis, rather than necrosis.
Adenoviridae↗
Should lungs from donors with severe acute pulmonary embolism be accepted for transplantation? The Hannover experience.
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Adolescent↗
In-situ topical cooling of lung grafts: early graft function and surfactant analysis in a porcine single lung transplant model.
OBJECTIVE: Improvement of organ preservation is essential to facilitate acceptance of marginal donor lungs for transplantation. Thus, recruiting non-heart-beating donors (NHBD) may be one reasonable strategy to augment the organ-pool especially in the field of pulmonary transplantation. Topical cooling (TC) of donor lungs could provide fast organ-protection and is an available procedure even in smaller centers. In this study transplanted lung function and surfactant activity in same lungs, which were preserved by TC, were assessed following transplantation. METHODS: Twelve porcine allogeneic single lung transplants were performed. Six lungs that were flush preserved through the antegrade route served as controls. The other six lungs were preserved by TC for 30 min after induction of cardiac arrest by repeated application of cold saline (8 degrees C) to both pleural cavities. Lungs of both groups were stored in LPD solution for 24 h at 8 degrees C. After transplantation, the recipient's right bronchus and right pulmonary artery were clamped. Major endpoints included early graft function over a period of 7 h. Hemodynamic measures and respiratory functions were recorded in 30-min intervals. Surfactant function was determined before transplantation and 2 h after reperfusion by broncho-alveolar lavage fluid analysis. RESULTS: Only four animals of the control-group survived the 7 h reperfusion period. Right heart failure occurred in two animals after 150 and 240 min of reperfusion. All six animals in the TC group survived the observation period. Pulmonary vascular resistance (p<0.01), pulmonary artery pressure (p=0.03), and lung tissue water content remained significantly lower in topically cooled allografts (p=0.01) vs. controls. Surfactant function after transplantation was comparable in both groups with a trend towards lower protein contents (p=0.07) in the broncho-alveolar fluid of grafts after TC. CONCLUSIONS: In-situ TC seems to be a reliable strategy to preserve lungs for up to 24 h. It even surpasses the results of LPD-perfused grafts in hemodynamic function and survival time.
Animals↗
Time-resolved computational protein biochemistry: solvent effects on interactions, conformational transitions and equilibrium fluctuations.
Solvent plays an important role in modulating internal motions of proteins. Here we present a computational method for including solvent effects on charge-charge interactions and on pathways between functional protein conformations, and examine solvent effects on equilibrium internal fluctuations in proteins. A computationally efficient charge reparametrisation method is presented that satisfactorily reproduces the electrostatic interactions present in a full continuum Poisson-Boltzmann representation. The application of charge reparametrisation in the calculation of a large-scale conformational transition pathway in a protein, annexin V, is illustrated. We also examine solvent effects on fast (picosecond timescale) internal protein dynamics. Nosé-Hoover dual heatbath molecular dynamics simulations are performed. These simulations allow the solvent region to be fixed at one temperature and the protein at another. The results of the Nosé-Hoover simulations on hydrated myoglobin confirm that the solvent temperature strongly influences the protein fluctuations. We consider to what extent the solvent can be considered to determine the high temperature protein dynamics.
Animals↗
Impact of human interleukin-10 on vector-induced inflammation and early graft function in rat lung transplantation.
This study was undertaken to examine the time course of human interleukin (hIL)-10 gene expression after transtracheal administration of adenoviral (Ad)hIL-10 and its effect on the early adenoviral proinflammatory cytokine response and on post-transplant lung function. Using a rat lung transplant model, we observed that lungs retrieved 12 h after the administration of AdhIL-10 were associated with significant improvement in post-transplant lung function. Shorter periods of transfection were associated with significantly elevated levels of tumor necrosis factor-alpha and macrophage inflammatory protein-2 in lung tissue, leading to an increased degree of injury. The release of proinflammatory cytokines secondary to the adenoviral vector was reduced by high-dose methylprednisolone (30 mg/kg) administered 3 h before transfection. Reduction in the early adenoviral inflammatory response was associated with significant improvement in post-transplant lung function when lungs were retrieved 6 or 12 h after transtracheal administration of AdhIL-10. Transtracheal administration of adenoviral-mediated hIL-10 to donor lungs is associated with a significant early inflammatory response that may enhance ischemia-reperfusion injury if insufficient hIL-10 is expressed in lung tissue before retrieval. The period between delivery of AdhIL-10 and lung retrieval can be reduced if the early inflammatory response is suppressed with methylprednisolone.
Adenoviridae↗
Melatonin acutely improves the neuroendocrine architecture of sleep in blind individuals.
In blind individuals, the absence of light cues results in disturbances of sleep and sleep-related neuroendocrine patterns. The Zeitgeber influence of light on the timing of sleep is assumed to be mediated by melatonin, a hormone of the pineal gland, whose secretion is inhibited by light and enhanced during darkness. Here, we investigated whether a single administration of melatonin improves sleep and associated neuroendocrine patterns in blind individuals. In a double-blind crossover study, 12 totally blind subjects received 5 mg melatonin and placebo orally 1 h before bedtime starting at 2300 h. The dose used enhanced blood melatonin concentrations to clearly supraphysiological levels. Melatonin increased total sleep time and sleep efficiency (P < 0.05, respectively) and reduced time awake (P < 0.05). The increment in total sleep time was primarily due to an increase in stage 2 sleep (P < 0.01) and a slight increase in rapid eye movement sleep (P < 0.06). Most important, melatonin normalized in parallel the temporal pattern of ACTH and cortisol plasma concentration. While after placebo, ACTH and cortisol levels did not differ between early and late sleep, melatonin induced the typical suppression of pituitary-adrenal activity during early sleep and a distinct rise during late sleep (P < 0.01, respectively). Cortisol nadir values were also decreased after melatonin (P < 0.05). We conclude from these data that in totally blind individuals the single administration of a clearly pharmacological dose of melatonin can improve sleep function by synchronizing in time the inhibition of pituitary-adrenal activity with central nervous sleep processes.
Adjuvants, Immunologic↗
Computational tools for analysing structural changes in proteins in solution.
Many important structural changes in proteins involve long-time dynamics, which are outside the timescale presently accessible by a straightforward integration of Newton's equations of motion. This problem is addressed with minimisation-based algorithms, which are applied on possible reaction pathways using atomic-detail models. For reasons of efficiency, an implicit treatment of solvent is imperative. We present the charge reparameterisation protocol, which is a method that approximates the interaction energies obtained by a numerical solution of the Poisson-Boltzmann equation. Furthermore, we present a number of methods that can be used to compute possible reaction pathways associated with a particular conformational change. Two of them, the self-penalty walk and the nudged elastic band method, define an objective function, which is minimised to find optimal paths. A third method, conjugate peak refinement, is a heuristic method, which finds minimum energy paths without the use of an explicit objective function. Finally, we discuss problems and limitations with these methods and give a perspective on future research.
Algorithms↗
High failure rate after valve-sparing aortic root replacement using the "remodeling technique" in acute type A aortic dissection.
BACKGROUND: Valve-sparing surgery including the replacement of the sinus of valsalvae were initially meant to be promising approaches in the treatment of acute type A aortic dissection. However, the long-term outcome after valve-sparing aortic root replacement in acute type A dissection is currently the subject of intense debate, and the evidence reported in the literature is sparse. Here we report on our experience on valve sparing aortic root replacement inpatients with acute type A dissection. METHODS: From August 1995 to November 2000, 30 patients with acute type A dissection received valve-sparing aortic root replacement. Two different techniques were performed: the "remodeling" technique, first described by Yacoub in 1983 (8 patients) and the "reimplantation" technique, initially described by David and Feindel, in 1992 (22 patients). Endpoints of the study were early and late mortality, as well as aortic valve-related complications and reoperations. RESULTS: The mean follow-up time was 22.6+/-15.4 months. The overall 30 day mortality was 17% (5/29) and the late mortality 4% (1/24). During the observation period, 4 patients had to be reoperated (n=3) for acute aortic valve regurgitation after aortic root remodeling and for acute aortic valve endocarditis (n=1) after aortic root reimplantation. In the 3 patients with acute aortic valve regurgitation, symptoms occurred 44, 24, and 17 months after the initial operation in these patients. Intraoperatively prolapsing aortic leaflets because of commissural detachment was found in all 3 cases. In all other patients the latest echocardiographic follow-up examination revealed freedom from aortic regurgitation higher than grade 1. CONCLUSIONS: The high failure rate of aortic root remodeling inpatients with acute type A aortic dissection is discouraging. Whether this technique should be applied in acute type A aortic dissection is questionable. In contrast, aortic root reimplantation lead to favorable midterm outcome. Thus, we recommend consideration of this technique for surgical treatment of patients with acute type A aortic dissection.
Acute Disease↗
Sleep forms memory for finger skills.
Practicing a motor skill triggers a process of memory consolidation that continues for hours after practice has ended, and becomes manifest in an improved skill at later testing. We used a sequential motor task (finger-to-thumb opposition task) to show that, in humans, the formation of motor skill memories essentially benefits from sleep. Independent of whether placed during daytime or nighttime, sleep after practice enhanced speed of sequence performance on average by 33.5% and reduced error rate by 30.1% as compared with corresponding intervals of wakefulness. The effect of sleep after learning proved to be stable when retesting was postponed for another night, to exclude effects of sleep loss and to assure that all subjects had sufficient sleep before retrieval testing. Also, the consolidating effect of sleep was specific for the motor sequence learned. It did not generalize to a similar sequence containing identical movement segments in a different order. Retention periods of wakefulness improved performance only moderately and only if placed during daytime. The observations demonstrate a critical role of sleep for storing and optimizing motor skills.
Adolescent↗
[Current status of lung transplantation: patients, indications, techniques and outcome].
BACKGROUND: Lung transplantation has evolved to a standard treatment modality for patients suffering from end-stage lung diseases. INDICATIONS: Accepted indications for lung transplantation include chronic obstructive pulmonary disease of the lung (COPD) and other causes of emphysema (i.e., alpha-1-antitrypsin deficiency), parenchymal diseases (i.e., idiopathic pulmonary fibrosis), genetic disorders such as cystic fibrosis, vascular diseases (i.e., primary pulmonary hypertension), chronic infectious diseases (i.e., bronchiectasis), as well as rare indications such as lymphangioleiomyomatosis or sarcoidosis. TREATMENT AND OUTCOME: This article reviews the current strategies in the treatment of lung transplant recipients, surgical techniques, limitations of and outcome after lung transplantation.
Adolescent↗
Brain potential signs of slowed stimulus processing following cholecystokinin in Parkinson's disease.
RATIONALE: Cholecystokinin (CCK) is a neuropeptide which is colocalized with dopamine (DA) in neurons of the mesolimbic-frontocortical and nigrostriatal DA system. In animals CCK enhances DA activity in these systems. OBJECTIVES: The present study examined the effects of a single intranasal administration of CCK-8 on auditory brain potential (AEP) signs of cognitive processing and on motor performance in patients with Parkinson's disease (PD), known to originate from degeneration of DA neurons primarily in the nigrostriatal DA system. METHODS: Thirteen PD patients were examined after medication withdrawal, on two occasions after administration of placebo and 25 microg CCK-8, and compared with healthy controls matched for age and sex. AEPs were recorded while subjects performed an attention task (oddball paradigm). RESULTS: In the placebo condition, AEPs in the PD patients did not show marked alteration but were rather comparable to those in the controls. In healthy controls, CCK-8 enhanced the P3 complex ( P<0.05) and shortened latencies of the N2 and P3 components of the AEP evoked by task relevant target stimuli ( P<0.05). Contrary to expectations, in PD patients these AEP components were distinctly delayed after CCK-8 ( P<0.05). Motor performance was not changed by CCK-8 in PD patients or in controls. CONCLUSION: Data indicate a deleterious rather than beneficial effect of CCK on cognitive processing in PD patients that might result from a prevailing effect of the neuropeptide on transmitter systems (e.g. GABAergic) other than the DA system.
Aged↗