Physiological and psychological effects of imagery techniques on health anxiety.

Previous research has shown that intrusions are part of the psychopathology of mental disorders. Imagery techniques seem to be an effective treatment of negative intrusions. Since negative mental imagery is part of health anxiety, the present study investigated the impact of imagery techniques on health anxiety. A total of 159 students with elevated scores in a health anxiety questionnaire watched an aversive film concerning a cancer patient and were randomly allocated to one of three interventions (positive imagery, imagery reexperiencing, imagery rescripting) or the control group. The intervention lasted 9 min. Physiological data (heart rate and cortisol) as well as psychological measures, such as mood ratings, health anxiety scores, and intrusions, were assessed during the appointment, while psychological measures were assessed over a period of 1 week after the intervention. Cortisol levels changed over time depending on the intervention. Heart rate changed during the 9-min interventions as well, with the fastest decrease during imagery rescripting. Moreover, negative mood and distress decreased after the intervention, while intrusions were reduced 1 week after the intervention in all groups equally. The results suggest that imagery rescripting is a promising technique that seems to activate a process of deep elaboration. Therefore, it might be an adequate way to target health anxiety symptoms such as anxiety, intrusions, and avoidance or safety-seeking behavior. Further studies should focus on imagery rescripting in clinical samples with health anxiety and target individual intrusive images to increase effectiveness. Nevertheless, the development of a long-term explanatory model of rescripting is needed.

[Rehabilitation standards for follow-up treatment and rehabilitation of patients with ventricular assist device (VAD)]. / Rehabilitationsstandards für die Anschlussheilbehandlung und allgemeine Rehabilitation von Patienten mit einem Herzunterstützungssystem (VAD - ventricular assist device).

The increasing use of ventricular assist devices (VADs) in terminal heart failure patients provides new challenges to cardiac rehabilitation physicians. Structured cardiac rehabilitation strategies are still poorly implemented for this special patient group. Clear guidance and more evidence for optimal modalities are needed. Thereby, attention has to be paid to specific aspects, such as psychological and social support and education (e.g., device management, INR self-management, drive-line care, and medication).In Germany, the post-implant treatment and rehabilitation of VAD Patients working group was founded in 2012. This working group has developed clear recommendations for the rehabilitation of VAD patients according to the available literature. All facets of VAD patients' rehabilitation are covered. The present paper is unique in Europe and represents a milestone to overcome the heterogeneity of VAD patient rehabilitation.

[Hemodynamics and physical capacity in patients with left ventricular assist devices : An overview]. / Hämodynamik und körperliche Belastbarkeit bei Patienten mit Linksherzunterstützungssystem : Ein Überblick.

In the course of time implantation of left ventricular assist devices (LVAD) has become an alternative to heart transplantation due to the enormous technical developments and miniaturization of these systems. Following implantation most patients show a significant improvement in their clinical condition and exercise capacity as measured by the New York Heart Association (NYHA) classification; nevertheless, exercise tolerance remains clearly limited even after LVAD implantation. The complex physiological and hemodynamic changes in LVAD patients both at rest and during exercise are ultimately not completely understood. The aim of this article is to describe the current state of scientific knowledge with respect to the physical capacity of patients with terminal heart failure after LVAD implantation at rest and during exercise. The influence of increasing the pump speed and continuous physical exercise training on the physical capacity in the long-term course is reviewed. The significance of new diagnostic tools, such as the non-invasive inert gas rebreathing method for measurement of cardiac output and arteriovenous oxygen difference (AVDO2) in assessment of the performance of LVAD patients is discussed.

Implantation of CardioWest total artificial heart for irreversible acute myocardial infarction shock.

Patients who develop cardiogenic shock after acute myocardial infarction have a very high mortality rate despite early reperfusion therapy. Hemodynamic stabilization can often only be achieved by implanting a mechanical circulatory support system. When, in cases representing expansive myocardial impairment without any chance of recovery, pharmacological therapy and the use of percutaneous assist devices have failed, the implantation of a total artificial heart is indicated. We report our first experiences with this extensive and innovative method of managing irreversible cardiogenic shock patients. The CardioWest total artificial heart was implanted in 5 patients (male; mean age, 50 years). All patients were in irreversible cardiogenic shock despite maximum dosages of catecholamines, an intra-aortic balloon pump and/or a femoro-femoral bypass. In all patients early reperfusion therapy was performed. After implantation of the Cardio West system, all dysfunctional organ systems rapidly recovered in all patients. Four of 5 patients underwent successful heart transplantation after a mean support time of 156 days. One patient died because of enterocolic necroses caused by an embolic event after termination of dicumarol therapy. In summary, our first experiences justify this extensive management in young patients who would otherwise have died within a few hours.

Initial experience with the medtronic ADVANTAGE valve prosthesis in the mitral position--clinical outcome and analysis of complications.

OBJECTIVE: The Medtronic ADVANTAGE prosthetic heart valve is a bileaflet mechanical heart valve which has two main design modifications. The prosthesis has an enlarged central orifice to improve blood flow characteristics and an asymmetric butterfly pivot recess with expanded outflow component designed to enhance the blood flow washing through the pivot region. This report summarizes the initial experience with 55 patients who underwent isolated mitral valve replacement. METHODS: We prospectively followed 55 patients undergoing mitral valve replacement with the Medtronic ADVANTAGE prosthesis in a single center study. All patients were operated on via a median sternotomy and a left atrial approach. RESULTS: The age of the patients at implant ranged from 42 years to 77 years with a mean of 61.8 years. Forty-five percent of the patients were male. Seventy-five percent of the patients were in NYHA functional class III or IV prior to valve replacement. The diameters of the implanted prostheses were as follows: 25 mm in 2 patients, 27 mm in 12 patients, 29 mm in 20 patients, and 31 mm in 21 patients. Coronary artery bypass grafting was performed with valve replacement in 16.4 % of patients and additional tricuspid repair in 10.9 %. After one year, 97.6 % and after two years 100 % of the included patients were in NYHA functional class I or II. All patients had Coumadin (warfarin) therapy postoperatively with a target INR range of 2.5 to 3.5, or 3.0 to 4.0. There were 4 thromboembolic events (7.3 %) in the early period and 2 late events (2.6 %). Episodes of valve thrombosis were not seen during the follow-up, which consisted of 76.5 patient years. The hemodynamic performance was favorable and within clinically acceptable ranges. The incidence of valve-related mortality and morbidity in this preliminary study was extremely low, indicating good clinical results comparable to those reported for other bileaflet valves. CONCLUSION: The ADVANTAGE valve is a safe and effective option for mitral valve replacement with a very low incidence of valve-related complications.

Results after orthotopic heart transplantation accepting donor hearts >50 years: experience at La Pitie Salpetriere, Paris.

INTRODUCTION: We sought to examine the results of orthotopic heart transplantation accepting hearts from donors >50 years of age with special regard to the usefulness of peripheral extracorporeal membrane oxygenation for posttransplant graft dysfunction. PATIENTS: Between January 2000 and December 2004, a total of 247 patients underwent orthotopic heart transplantation. In 143 patients (58%) the heart donor was <50 years (group I, mean age of donor hearts 36 +/- 11 years; range, 8-49 years). In 104 recipients (42%) the heart donor was >50 years (group II, mean age of donor hearts 56 +/- 15 years; range, 50-67 years). Pretransplant characteristics of the two groups showed no significant differences. RESULTS: The in-hospital mortality was slightly increased in group II (24% vs 20% in group I, NS) and the 5-year survival rate significantly increased in group I (75% vs 63% in group II). Freedom from transplant vasculopathy after 3 years was similar in both groups (86% in group I vs 87% in group II). A total of 25 patients (17%) in group I and 27 patients (26%) in group II developed graft dysfunction. Eleven patients in group I and 10 patients in group II were treated using peripheral extracorporeal membrane oxygenation, whereas 3 of the 11 patients in group I and 5 of the 10 patients in group II were discharged following a complete recovery. Two patients in group I and 4 patients in group II were survivors beyond year. CONCLUSION: In our experience it was possible to increase the cardiac donor pool by accepting allografts from donors >50 years of age in selected cases. The incidence of transplant vasculopathy was not increased, whereas in-hospital mortality was slightly higher. In our limited cohort, patients with older donor hearts was developed graft dysfunction profited from primary extracorporeal membrane oxygenation implantation, an indication that should be examined further without delay.

Mechanical valve replacement in congenital heart defects in the era of international normalized ratio self-management.

As the number of patients with congenital heart defects requiring heart valve replacement increases, the need for durable valve substitutes with good hemodynamic performance and a low incidence of complications becomes more apparent. The use of porcine xenografts is burdened with early fibrocalcific degeneration, whereas the use of mechanical heart valves led to an increased number of thromboembolic events, especially when implanted in the right side of the heart. We report on our experiences implanting bileaflet heart valves in congenital heart defects since the introduction of international normalized ratio (INR) self-management. The data of 68 long-term survivors (33 males, 35 females) who underwent mechanical heart valve replacement in congenital heart defect were reviewed. Patient age at the time of valve replacement ranged from 5 months to 61 years (mean 21 years). Underlying diagnoses were tetralogy of Fallot (n=33), morbus Ebstein (n=4), atrioventricular canal (n=13), truncus arteriosus communis (n=5), transposition of the great arteries (n=10), and congenitally corrected transposition of the great arteries (n=3). In all patients, bileaflet valves were implanted (St. Jude Medical n=40, Carbomedics n=28). Anticoagulation was performed using dicumarol (Marcumar) and INR self-management in all cases. The mean follow-up was 72 months (range 6-132 months; 409 patient-years). Valve thrombosis developed in 3 of 68 patients (4.4%, all three had tetralogy of Fallot, mean age 9.8 years) after a mean follow-up of 3.5 years. In two of these three patients, re-pulmonary valve replacement was necessary, whereas the third patient was treated by thrombolysis. From our experience, we conclude that mechanical heart valve replacement is a good therapy option with a low complication rate for patients with congenital heart defects requiring valve replacement, especially when INR self-management is performed.

[Implantation of CardioWest total artificial heart in irreversible acute myocardial infarction shock-new hope for patients with infaust prognosis]. / Einsatz des CardioWest-Kunstherzens beim irreversiblen kardiogenen Schock nach Myokardinfarkt. Eine Hoffnung für Patienten mit infauster Prognose.

Patients in whom cardiogenic shock develops after acute myocardial infarction have a very high death rate despite early reperfusion therapy. Often hemodynamic stabilization can be achieved only by implantation of a mechanical circulatory support system. When pharmacological therapy and onset of percutaneous assist devices fails in cases representing expansive myocardial impairment without any chance of recovery, the indication for implanting a total artificial heart is given. We report on our first experiences with this extensive and innovative management of irreversible cardiogenic shock patients. In five patients (male, mean age 50 years) the CardioWest total artificial heart was implanted. All patients were in irreversible cardiogenic shock despite maximal dosages of catecholamines, intraaortic balloon pump and/or femorofemoral bypass. In all patients early reperfusion therapy was performed. After implantation of the CardioWest system, rapid recovery of all dysfunctional organ systems occurred in all patients. Four of five patients underwent successful heart transplantation after a mean support time of 156 days. One patient died because of enterocolic necroses caused by embolic event after termination of dicumarol therapy. In summary, first experiences justify this extensive management in these young patients who otherwise would have died within a few hours.

Biphasic modulation of protein kinase C and enhanced cell toxicity by amyloid beta peptide and anoxia in neuronal cultures.

A major feature of Alzheimer's disease is the deposition of the amyloid beta peptide (Abeta) in the brain by mechanisms which remain unclear. One hypothesis suggests that oxidative stress and Abeta aggregation are interrelated processes. Protein kinase C, a major neuronal regulatory protein is activated after oxidative stress and is also altered in the Alzheimer's disease brain. Therefore, we examined the effects of Abeta(1-40) peptide on the protein kinase C cascade and cell death in primary neuronal cultures following anoxic conditions. Treatment with Abeta(1-40) for 48 h caused a significant increase in the content and activity of Ca2+ dependent and Ca2+ independent protein kinase C isoforms. By 72 h various protein kinase C isoforms were down-regulated. Following 90 min anoxia and 6 h normoxia, a decrease in protein kinase C isoforms was noticed, independent of Abeta(1-40) treatment. A combination of Abeta(1-40) and 30-min anoxia enhanced cytotoxicity as noticed by a marked loss in the mitochondrial ability to convert 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and by enhanced 4',6-diamidino-2-phenylindole nuclear staining. Phosphorylation of two downstream protein kinase C substrates of apparent molecular mass 80 and 43 kDa, tentatively identified as the myristoyl alanine-rich C-kinase substrate (MARCKS), were gradually elevated up to 72 h upon incubation with Abeta(1-40). Anoxia followed by 30 min normoxia enhanced MARCKS phosphorylation in the membrane but not in the cytosolic fraction. In the presence of Abeta(1-40), phosphorylation of MARCKS was reduced. After 6 h normoxia, MARCKS phosphorylatability was diminished possibly because of protein kinase C down-regulation. The data suggest that a biphasic modulation of protein kinase C and MARCKS by Abeta(1-40) combined with anoxic stress may play a role in Alzheimer's disease pathology.

Implantation of the Biomedicus centrifugal pump in post-transplant right heart failure.

BACKGROUND: Right heart failure after heart transplantation represents a life-threatening complication. When conventional therapy including NO-inhalation fails the only choice to reach sufficient haemodynamic conditions may be the implantation of a right ventricular support system. METHODS: In all cases the Biomedicus centrifugal pump was implanted by cannulation of the right atrium and pulmonary artery. RESULTS: Since March 1989 950 heart transplant procedures were performed at our center. In nine cases (7 male, 2 female, mean age 52 years) implantation of a right ventricular support system was necessary because of deterioration of right ventricular function. The implantation was carried out in 7 cases immediately after transplantation, in 2 cases after 2 days. The support time ranged from 4-348 hours. Six patients could be weaned, 2 patients underwent retransplantation and died and 1 patient died on the support system. Three of the six weaned patients died in the further course because of multiorgan failure. CONCLUSIONS: Mechanical right ventricular support is often the only therapeutical tool to reach adequate haemodynamic conditions in post-transplant right heart failure. The Biomedicus centrifugal pump provides good conditions in these cases. Weaning is often possible after short-term support. The mortality rate is determined by multiorgan failure in immuno-suppressed patients. Retransplantation seems not to be successful despite maximal treatment.

Thoracic and cardiovascular interventions after orthotopic heart transplantation.

BACKGROUND: The long-term outcome of orthotopic heart transplantation is limited by the development of cardiac allograft vasculopathy, rejection, infection, and malignancy. METHODS: After heart transplantation, we treated patients with thoracic and cardiovascular diseases: preexisting coronary artery sclerosis in 2 patients, cardiac allograft vasculopathy in 19, valvular disease in 3, mycotic ascending aortic aneurysm in 2, superior vena cava stenosis in 2, and lung neoplasm in 10 patients. RESULTS: We successfully performed coronary artery bypass grafting for preexisting coronary artery sclerosis, valve replacement for valvular disease, and patch enlargement for superior vena cava stenosis. Percutaneous transluminal coronary angioplasty for cardiac allograft vasculopathy achieved excellent initial results, but the incidence of restenosis was high (67%). One patient who underwent coronary artery bypass grafting for cardiac allograft vasculopathy died immediately after operation. Graft replacement was performed for mycotic aortic aneurysm, but 1 patient required reoperation because of recurrent aneurysm. The long-term survival rate in patients undergoing surgical resection for lung neoplasm was poor (50%). CONCLUSIONS: The need for thoracic and cardiovascular interventions in patients after heart transplantation was low (4.7%). Use of the appropriate procedures can improve the long-term survival after heart transplantation.

Activation of Go-proteins by membrane depolarization traced by in situ photoaffinity labeling of galphao-proteins with [alpha32P]GTP-azidoanilide.

Evidence for depolarization-induced activation of G-proteins in membranes of rat brain synaptoneurosomes has been previously reported (Cohen-Armon, M., and Sokolovsky, M. (1991) J. Biol. Chem. 266, 2595-2605; Cohen-Armon, M., and Sokolovsky, M. (1993) J. Biol. Chem. 268, 9824-9838). In the present work we identify the activated G-proteins as Go-proteins by tracing their depolarization-induced in situ photoaffinity labeling with [alpha32P]GTP-azidoanilide (GTPAA). Labeled GTPAA was introduced into transiently permeabilized rat brain-stem synaptoneurosomes. The resealed synaptoneurosomes, while being UV-irradiated, were depolarized. Relative to synaptoneurosomes at resting potential, the covalent binding of [alpha32P]GTPAA to Galphao1- and Galphao3-proteins, but not to Galphao2- isoforms, was enhanced by 5- to 7-fold in depolarized synaptoneurosomes, thereby implying an accelerated exchange of GDP for [alpha32P]GTPAA. Their depolarization-induced photoaffinity labeling was independent of stimulation of Go-protein-coupled receptors and could be reversed by membrane repolarization, thus excluding induction by transmitters release. It was, however, dependent on depolarization-induced activation of the voltage-gated sodium channels (VGSC), regardless of Na+ current. The alpha subunit of VGSC was cross-linked and co-immunoprecipitated with Galphao-proteins in depolarized brain-stem and cortical synaptoneurosomes. VGSC alpha subunit most efficiently cross-linked with guanosine 5'-O-2-thiodiphosphate-bound rather than to guanosine 5'-O-(3-thiotriphosphate)-bound Galphao-proteins in isolated synaptoneurosomal membranes. These findings support a possible involvement of VGSC in depolarization-induced activation of Go-proteins.

Development and initial in vivo testing of a new hydraulic drive system (Paedipump) for circulatory support in infants.

The main limitation in the use of circulatory support in children is the lack of an adequate system with regard to size and pumping capacity. Recently, two pneumatically driven ventricular support systems with low volume chambers for use in a pediatric population became available. We have developed a hydraulic drive system with an advantageous exact control of the stroke volume. The system enables two different modes of operation: the full-empty and the filled-empty modes. In both cases the ventricle is empty at the end of systole. This new system was tested in experimental animals (6 pigs, body weight 9.5-14.0 kg) with normal and reduced left ventricular function (MAP<45 mmHg). A 25 ml ventricle (HIA-Medos) was implanted. The full-empty and the filled-empty mode used led to a significant load reduction, both in animals with normal and impaired cardiac function. Plasma lactate levels, pH-values and total body O2-consumption were in the normal range during circulatory support indicating adequate organ perfusion. Results showed that sufficient ventricular support was achieved during all pumping modes due to the possibility of controlling and modifying the stroke volume of the hydraulically driven support system employed according to necessity. This is a promising feature for its future application in infants with congenital or acquired heart diseases.

Stimulation of Jun N-terminal kinase (JNK) by gonadotropin-releasing hormone in pituitary alpha T3-1 cell line is mediated by protein kinase C, c-Src, and CDC42.

The signaling of ligands operating via heterotrimeric G proteins is mediated by a complex network that involves sequential phosphorylation events. Signaling by the G protein-coupled receptor GnRH was shown to include elevation of Ca2+ and activation of phospholipases, protein kinase C (PKC) and extra-cellular signal-regulated kinase (ERK). In this study, GnRH was shown to activate Jun N-Terminal Kinase (JNK)/SAPK in alpha T3-1 cells in a PKC- and tyrosine kinase-dependent manner. GnRH as well as tumor-promoting agent (TPA) also increased c-Src activity, which peaked at 2 min after GnRH stimulation and was sensitive both to PKC and to tyrosine kinase inhibitors. Coexpression of Csk, which serves as a Src-dominant interfering kinase, and constitutively active forms of Src, together with JNK, confirmed the involvement of c-Src downstream of PKC in the GnRH-JNK pathway. Coexpression of dominant negative and constitutively active forms of CDC42, Rac1, Ras, MEKK1, and MEK1 with JNK indicated that JNK activation by GnRH and TPA is mediated by CDC42 and MEKK1. Ras and MEK1, which are involved in a related mitogen-activated protein kinase (MAPK) pathway, did not affect JNK activation in alpha T3-1 cells. Taken together, our results suggest that GnRH stimulation of JNK activity is mediated by a unique pathway that includes sequential activation of PKC, c-Src, CDC42, and probably also MEKK1.

Differential activation of protein kinase C delta and epsilon gene expression by gonadotropin-releasing hormone in alphaT3-1 cells. Autoregulation by protein kinase C.

The effect of gonadotropin-releasing hormone (GnRH) upon protein kinase C (PKC) delta and PKCepsilon gene expression was investigated in the gonadotroph-derived alphaT3-1 cell line. Stimulation of the cells with a stable analog [D-Trp6]GnRH (GnRH-A) resulted in a rapid elevation of PKCepsilon mRNA levels (1 h), while PKCdelta mRNA levels were elevated only after 24 h of incubation. The rapid elevation of PKCepsilon mRNA by GnRH-A was blocked by pretreatment with a GnRH antagonist or actinomycin D. The PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA), but not the Ca2+ ionophore ionomycin, mimicked the rapid effect of GnRH-A upon PKCepsilon mRNA elevation. Additionally, the rapid stimulatory effect of GnRH-A was blocked by the selective PKC inhibitor GF109203X, by TPA-mediated down-regulation of endogenous PKC, or by Ca2+ removal. Interestingly, serum-starvation (24 h) advanced the stimulation of PKCdelta mRNA levels by GnRH-A and the effect could be detected at 1 h of incubation. The rapid effect of GnRH-A upon PKCdelta mRNA levels in serum-starved cells was mimicked by TPA, but not by ionomycin, and was abolished by down-regulation of PKC or by Ca2+ removal. Preactivation of alphaT3-1 cells with GnRH-A for 1 h followed by removal of ligand and serum resulted in elevation of PKCdelta mRNA levels after 24 h of incubation. Western blot analysis revealed that GnRH-A and TPA stimulated (within 5 min) the activation and some degradation of PKCdelta and PKCepsilon. We conclude that Ca2+ and PKC are involved in GnRH-A elevation of PKCdelta and PKCepsilon mRNA levels, with Ca2+ being necessary but not sufficient, while PKC is both necessary and sufficient to mediate the GnRH-A response. A serum factor masks PKCdelta but not PKCepsilon mRNA elevation by GnRH-A, and its removal exposes preactivation of PKCdelta mRNA by GnRH-A which can be memorized for 24 h. PKCdelta and PKCepsilon gene expression evoked by GnRH-A is autoregulated by PKC, and both isotypes might participate in the neurohormone action.

Mechanism of mitogen-activated protein kinase activation by gonadotropin-releasing hormone in the pituitary of alphaT3-1 cell line: differential roles of calcium and protein kinase C.

The mechanism of mitogen-activated protein kinase (MAPK, ERK) stimulation by the GnRH analog [D-Trp6]GnRH (GnRH-a) was investigated in the gonadotroph-derived alphaT3-1 cell line. GnRH-a as well as the protein kinase C (PKC) activator 12-O-tetradecanoyl phorbol-13-acetate (TPA) stimulated a sustained response of MAPK activity, whereas epidermal growth factor (EGF) stimulated a transient response. MAPK kinase (MEK) is also activated by GnRH-a, but in a transient manner. GnRH-a and TPA apparently activated mainly the MAPK isoform ERK1, as revealed by Mono-Q fast protein liquid chromatography followed by Western blotting as well as by gel kinase assay. GnRH-a and TPA stimulated the tyrosine phosphorylation of several proteins, and this effect as well as the stimulation of MAPK activity were inhibited by the PKC inhibitor GF 109203X. Similarly, down-regulation of TPA-sensitive PKC subspecies nearly abolished the effect of GnRH-a and TPA on MAPK activity. Furthermore, the protein tyrosine kinase (PTK) inhibitor genistein inhibited protein tyrosine phosphorylation and reduced GnRH-a-stimulated MAPK activity by 50%, suggesting the participation of genistein-sensitive and insensitive pathways in GnRH-a action. Although Ca2+ ionophores have only a marginal stimulatory effect, the removal of Ca2+ markedly reduced MAPK activation by GnRH-a and TPA, but had no effect on GnRH-a and TPA stimulation of protein tyrosine phosphorylation. Interestingly, the removal of Ca2+ also partly inhibited the activation of MAPK by EGF and vanadate/H2O2. Thus, a calcium-dependent component(s) downstream of PKC and PTK might also participate in MAPK activation. Elevation of cAMP by forskolin exerted partial inhibition on EGF, but not on TPA or GnRH-a action, suggesting that MEK activators other than Raf-1 might be involved in GnRH action. We conclude that Ca2+, PTK, and PKC participate in the activation of MAPK by GnRH-a, with Ca2+ being necessary downstream to PKC and PTK.

Phosphatidylserine directs differential phosphorylation of actin and glyceraldehyde-3-phosphate dehydrogenase by protein kinase C: possible implications for regulation of actin polymerization.

The phospholipid-dependent protein kinase C is implicated in the regulation of cellular motility and energy metabolism. Phosphatidylserine, a main cofactor of protein kinase C, is involved in the regulation of glyceraldhehyde-3-phosphate dehydrogenase, which as actin, was shown to be phosphorylated by purified protein kinase C. Here, we study the effect of phosphatidylserine on the enzyme-substrate interaction of protein kinase C with glyceraldhehyde-3-phosphate dehydrogenase and actin. The stoichiometry of glyceraldhehyde-3-phosphate dehydrogenase phosphorylation is not affected by varying the level of phosphatidylserine. However, actin phosphorylation is dependent on phosphatidylserine level, peaking at high phosphatidylserine concentration. Moreover, if actin and glyceraldhehyde-3-phosphate dehydrogenase are cophosphorylated at high phosphatidylserine concentration, actin phosphorylation is favored, despite lower affinity for protein kinase C. Hence, phosphatidylserine directs differential phosphorylation of these key proteins of glycolysis and cellular motility and might be capable of recruiting protein kinase C for preferential actin phosphorylation. The sedimentation of phosphorylated actin is increased 3.8 fold and total actin 1.7 fold, suggesting that phosphorylation promotes actin polymerization.

Transport of hemodynamically unstable patients by a mobile mechanical circulatory support team.

Advances in medical technology have made it possible to use emergency femoro-femoral bypass (FFB) for transport of hemodynamically unstable patients. In this study, we report on our experience of transport of patients with refractory heart failure by a special mobile mechanical circulatory support team (MMCST) using an intraaortic balloon pump (IABP) or FFB. A total of 22 patients (14 men, 8 women) were supported by the MMCST and transported to our clinic for further diagnostic or therapeutic procedures. The diagnoses in 12 patients was acute myocardial infarction, in 7 patients, dilatative cardiomyopathy (DCM), and in 3 patients, acute fulminant myocarditis. In 15 cases, FFB was implanted (5 in combination with IABP), and in 5 cases, IABP only was implanted. Two patients received maximal dosages of catecholamines. After arrival at our clinic, 11 patients received implants of a more sophisticated support system. From the myocardial infarction group, 3 patients received coronary artery bypass grafting, 1 patient received percutaneous transluminal coronary angioplasty, and 1 patient received heart transplantation as final therapy. In the myocarditis and DCM groups, 7 patients underwent heart transplantation. Finally, 11 patients (50%) survived, and 11 patients died of multiorgan failure or septicemia.

Management of acute fulminant myocarditis using circulatory support systems.

Although the natural history of acute myocarditis leads to complete recovery in the majority of patients, rapid and irreversible cardiac decompensation resulting in death is known to occur. One possible therapy to improve the poor prognosis of this patient group may be the implantation of circulatory support systems that allow myocardial recovery or bridging to heart transplantation. Therapeutic protocols have been suggested, but clinical experiences in this area are few. In this paper we report on our clinical experiences in cardiogenic shock after acute fulminant myocarditis using different types of circulatory support systems. Three different systems were used: a biomedicus centrifugal pump as a ventricular assist device (VAD) or femoro-femoral bypass (FFB) including oxygenator; Abiomed BVS 5000, and Thoratec ventricular assist device. Hemodynamic criteria for implantation of support systems were cardiac index < 2.0 L/min/m2. SVR = 1000 dyne-s-cm-5, central venous pressure (CVP) or left atrial pressure (LAP) > 20 mm Hg, and urine output < 20 ml/h despite maximal pharmacological therapy. Age total of 5 patients (mean age 29 years, range 15-55 years) in cardiogenic shock after acute fulminant myocarditis were included. Two patients initially were supported for stabilization and transportation from an outside hospital by FFB. Both patients died after a support time of 24 h because of multiorgan failure or neurological disorders after longer periods of resuscitation in the referral hospital. The third patient (55 years) received the Biomedicus pump as CVAD. Myocardial function recovered after a support time of 120 h, and the patient could be weaned. Unfortunately, 2 days after weaning, he developed malignant arrhythmias and died. The 2 remaining patients (15 years and 27 years) with diagnosis of acute fulminant virus myocarditis were supported by biventricular assist device (1 x Thoratec/111 days, 1 x Abiomed/7 days). During the entire time of support, there were no signs of myocardial recovery. The patients were accepted for the heart transplantation (HTX) program. In both cases, HTXs were performed without any complication. The postoperative course was uneventful. The results of mechanical circulatory support in patients with acute fulminant myocarditis are encouraging and justify the resources.

Clinical, biochemical, and genetic findings in a large pedigree of male and female patients with 5 alpha-reductase 2 deficiency.

The present report describes a cluster of eight patients with male pseudohermaphroditism from a large pedigree with steroid 5 alpha-reductase 2 deficiency (5 alpha RD), who reside in Southern Lebanon. They were born with unambiguous female external genitalia and reared as girls until puberty, when masculinization occurred, followed by a change of gender role. Semen analysis and testicular histology revealed maturation arrest of spermatogenesis, with low sperm count and motility. Determination of urinary 5 alpha- and 5 beta-reduced adrenal steroids enabled us to diagnose the disease in a male patient with the full-blown clinical syndrome, in another male patient who had undergone bilateral orchidectomy, and in three female individuals with the biochemical derangement. The female patients were unique in this family with respect to their low degree of virilization, but had normal menstrual cycles. Molecular genetic studies were performed on DNA extracted from peripheral leukocytes and from cultured genital skin fibroblasts. The coding sequence of the 5 alpha R2 gene (SRD5A2) was studied by exon-specific PCR, single strand conformation polymorphism, and direct sequencing. A homozygous point mutation was identified in exon 1, leading to a thymidine for adenine substitution, predicting amino acid substitution of leucine for glutamine at position 55.