Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits.

Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of a spectrum of anxiety disorders, yet paradoxically they may increase symptoms of anxiety when treatment is first initiated. Despite extensive research over the past 30 years focused on SSRI treatment, the precise mechanisms by which SSRIs exert these opposing acute and chronic effects on anxiety remain unknown. By testing the behavioral effects of SSRI treatment on Pavlovian fear conditioning, a well characterized model of emotional learning, we have the opportunity to identify how SSRIs affect the functioning of specific brain regions, including the amygdala, bed nucleus of the stria terminalis (BNST) and hippocampus. In this review, we first define different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. We examine the results of numerous rodent studies investigating how acute SSRI treatment modulates fear learning and relate these effects to the known functions of serotonin in specific brain regions. With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning. Finally, we review the literature examining the effects of chronic SSRI treatment on fear conditioning in rodents and describe how downregulation of N-methyl-d-aspartate (NMDA) receptors in the amygdala and hippocampus may mediate the impairments in fear learning and memory that are reported. While long-term SSRI treatment effectively reduces symptoms of anxiety, their disruptive effects on fear learning should be kept in mind when combining chronic SSRI treatment and learning-based therapies, such as cognitive behavioral therapy.

A role for the extended amygdala in the fear-enhancing effects of acute selective serotonin reuptake inhibitor treatment.

Selective serotonin reuptake inhibitors (SSRIs) are reported to exacerbate symptoms of anxiety when treatment is initiated. These clinical findings have been extended to animal models wherein SSRIs also potentiate anxiety and fear learning, which depend on the amygdala. Yet, little is known about the role of specific amygdalar circuits in these acute effects of SSRIs. Here, we first confirmed that a single injection of fluoxetine 1 h before auditory fear conditioning potentiated fear memory in rats. To probe the neural substrates underlying this enhancement, we analyzed the expression patterns of the immediate early gene, Arc (activity-regulated cytoskeleton-associated protein). Consistent with previous reports, fear conditioning induced Arc protein expression in the lateral and basal amygdala. However, this was not enhanced further by pre-treatment with fluoxetine. Instead, fluoxetine significantly enhanced expression of Arc in the central amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). Next, we tested whether direct targeted infusions of fluoxetine into the CeA, or BNST, leads to the same fear-potentiating effect. Strikingly, direct infusion of fluoxetine into the BNST, but not the CeA, was sufficient to enhance fear memory. Moreover, this behavioral effect was also accompanied by robust Arc expression in the CeA, similar to the systemic injection. Our results identify a novel role for the BNST in the acute fear-enhancing effects of SSRIs. These findings highlight the need to look beyond the traditional focus on input nuclei of the amygdala and add to accumulating evidence implicating these microcircuits in gating fear and anxiety.

Pre- and postoperative assessment of left ventricular function by magnetic resonance imaging and 2-D-echocardiography in patients undergoing left ventricular aneurysmectomy.

BACKGROUND: Left ventricular (LV) aneurysms may complicate myocardial infarctions. Reliable quantification of LV functional parameters is mandatory to predict clinical outcome in patients undergoing LV aneurysmectomy. We compared global LV function measured by magnetic resonance (MR) and 2-D-echocardiography in patients before and after aneurysmectomy. METHODS: 31 patients (23 male), mean age 64 (range 35 - 85) years with an LV aneurysm (25/31 anterior MI, 5/31 inferior MI, 1/31 both) were enrolled. MR and echocardiography were performed directly before and 3 - 65 (median 8) days after surgery. MR studies were performed on a 1.5 Tesla scanner. End-diastolic and end-systolic volumes and diameters (EDV/ESV, EDD/ESD), ejection fraction (EF) and stroke volume (SV) were determined. Echocardiography was performed to determine EF, EDD and ESD. NYHA class was assessed before and 3 months after surgery. RESULTS: After aneurysmectomy MR analysis showed a decrease in EDV (255 +/- 68 ml to 202 +/- 59 ml) ( p < 0.001) and ESV (186 +/- 71 ml to 134 +/- 53 ml; p < 0.001); EF increased (28 +/- 10 % to 35 +/- 12 %; p < 0.001); EDD/ESD decreased ( p < 0.01). Compared to echocardiography, a low correlation was found in EF before/after surgery r = 0.76/r = 0.69 and ESD r = 0.43/r = 0.60, respectively. In EDD a good correlation was found before surgery (r = 0.81), and a lower correlation after surgery (r = 0.72). NYHA class improved from 3.0 +/- 0.5 before to 1.8 +/- 0.8 after operation ( p < 0.001). CONCLUSION: Resection of an LV aneurysm results in a mean improvement of 25 % in LV function, and improved clinical outcome. In asymmetric ventricles with aneurysms MR proved to be superior as a sensitive and non-invasive tool compared to conventional 2-D-echocardiography.

Leukocyte-depleted secondary blood cardioplegia attenuates reperfusion injury after myocardial ischemia.

BACKGROUND: Activated neutrophils have been implicated in reperfusion injury of the myocardium; leukocyte depletion at the time of reperfusion may contribute to better myocardial protection after cardiac surgery. In the present study, we examined whether leukocyte depletion as an adjunct to terminal blood cardioplegia attenuates reperfusion injury. METHODS: Porcine hearts that had undergone 60 minutes of normothermic ischemia with cardioplegia and 60 minutes of reperfusion under cardiopulmonary bypass were divided into four groups according to the methods of 15 min of controlled initial reperfusion: whole blood reperfusion (n = 6), leukocyte-depleted reperfusion (n = 6), secondary blood cardioplegia (n = 6) and leukocyte-depleted secondary blood cardioplegia (n = 6). At 60 min of reperfusion, hemodynamic recovery, release of malondialdehyde (MDA) as a marker for free oxygen radicals, CK-MB-isoenzyme from the coronary sinus, recovery of adenosine triphosphate, and myocardial water content were evaluated. RESULTS: The group with leukocyte-depleted secondary blood cardioplegia showed the best hemodynamic recovery (Emax and total dp/dt), lowest levels of MDA, CK-MB and myocardial water content, and highest adenosine triphosphate recovery. CONCLUSIONS: These results suggest that controlled reperfusion with leukocyte-depleted secondary blood cardioplegia attenuated severe damage of the myocardium as compared to whole blood reperfusion.

Novadaq Spy Intraoperative Imaging System--current status.

The Novadaq Spy Intraoperative Imaging System is able to depict a fluorescent contrast agent emitting light at 830 nm when passing through the vascular tree or through myocardial chambers. The passage of the contrast agent can be observed in real time, allowing quality control in adult and congenital cardiovascular surgery.

Contrast-echocardiography: confirmation of patency of laser channels after transmyocardial laser revascularization.

AIMS: Apart from casuistic autopsy results there is no long-term evidence for channel perfusion after transmyocardial laser revascularization in humans. METHODS AND RESULTS: Fifteen consecutive patients aged 63+/-17 years were investigated 71+/-15 days after coronary artery bypass surgery and/or transmyocardial revascularization with 13-37 (20+/-5) channels (CO(2) laser, 40 J/pulse). Echocardiography was performed after injection of 6 ml echo contrast medium into left ventricular cavity and after injection of 3 ml contrast medium into the left main coronary artery. In five patients with additional bypass surgery to the same region, we also injected 3 ml contrast medium into bypass graft. We could prove in 10 of 15 patients (67%) one or two laser channels in the apical left ventricular myocardium. Channels were perfused exclusively during systole. During following heart cycles myocardium was opacified up to a mean width of 1.4+/-0.4 cm, a mean depth of 0.71+/-0.1cm, and a mean area of 1.0+/-0.6 cm(2). Contrast medium was washed out via coronary venous system in 9+/-8 systoles. CONCLUSION: This is the first clinical evidence of long-term laser-channel patency in humans showing perfused myocardium via left ventricular cavity.

Predictors for atrial transport function after mini-maze operation.

BACKGROUND: Restoration of atrial transport function (ATF) is a major goal of the maze procedure. This prospective study was undertaken to evaluate predictors of left atrial transport function in patients undergoing a mini-variant of the maze III procedure 3 and 12 months postoperatively. METHODS: Mini-maze operation was performed in 72 patients with a mean age of 64 +/- 8.7 years during a 5-year period. Seventy of 72 (97%) had combined procedures. Clinical and electrophysiologic examination was carried out before surgery, and 3 and 12 months postoperatively. RESULTS: Early mortality was 1.4% (1 of 72 patients) and late death occurred in 5.6% (4 of 71 patients). After 3 months, 54 of 68 (80%) patients showed sinus rhythm, and 48 of 60 (80%) after 12 months. ATF was restored in 87% (echocardiography) and 82% (magnetic resonance imaging) after 3 months, and in 86% (echocardiography) and 78% (magnetic resonance imaging) after 12 months. Independent predictors for ATF restoration after 12 months were better preoperative left ventricular function (p = 0.02), and smaller preoperative left atrial diameter (p = 0.005). Correlation between echocardiography and magnetic resonance imaging was 80% after 12 months. CONCLUSIONS: Restoration of ATF after mini-maze procedure is achieved in over 80%. Independent predictors for ATF restoration are smaller preoperative left atrial diameter and better preoperative left ventricular ejection fraction.

Ruptured papillary muscle after mitral valve replacement with preservation of chordae tendineae.

Many cardiac surgeons believe strongly that every effort should be made to preserve the continuity of the mitral anulus, chordae tendineae, and papillary muscles during mitral valve replacement in order to maximize ventricular function and maintain normal ventricular geometry. We treated a patient with spontaneous papillary muscle rupture after mitral valve replacement in whom efforts had been made to preserve continuity of the mitral mechanism.

Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning.

Fear conditioning is a form of associative learning in which subjects come to express defense responses to a neutral conditioned stimulus (CS) that is paired with an aversive unconditioned stimulus (US). Considerable evidence suggests that critical neural changes mediating the CS-US association occur in the lateral nucleus of the amygdala (LA). Further, recent studies show that associative long-term potentiation (LTP) occurs in pathways that transmit the CS to LA, and that drugs that interfere with this LTP also disrupt behavioral fear conditioning when infused into the LA, suggesting that associative LTP in LA might be a mechanism for storing memories of the CS-US association. Here, we develop a detailed cellular hypothesis to explain how neural responses to the CS and US in LA could induce LTP-like changes that store memories during fear conditioning. Specifically, we propose that the CS evokes EPSPs at sensory input synapses onto LA pyramidal neurons, and that the US strongly depolarizes these same LA neurons. This depolarization, in turn, causes calcium influx through NMDA receptors (NMDARs) and also causes the LA neuron to fire action potentials. The action potentials then back-propagate into the dendrites, where they collide with CS-evoked EPSPs, resulting in calcium entry through voltage-gated calcium channels (VGCCs). Although calcium entry through NMDARs is sufficient to induce synaptic changes that support short-term fear memory, calcium entry through both NMDARs and VGCCs is required to initiate the molecular processes that consolidate synaptic changes into a long-term memory.

[Papillary muscle rupture after mitral valve replacement with preservation of subvalvular structures]. / Papillarmuskelruptur nach Mitralklappenersatz mit erhaltenem subvalvulärem Apparat.

We report a female patient with mitral valve replacement and preservation of subvalvular apparatus in which parts of the papillary muscle ruptured postoperatively. During systole the ruptured papillary muscle prolapsed through the native aortic valve. Echocardiographic documentation and operative procedure were demonstrated.

Epidemiology of occupational injuries and illnesses in a university population: a focus on age and gender differences.

BACKGROUND: Occupational injuries and illnesses are a major preventable public health problem. METHODS: This study evaluated the incidence, nature, and cause of awarded workers' compensation claims for a large state university and teaching hospital. Rates and types of injury were compared across age and gender. RESULTS: Rates of injury varied over twofold with age, with those 16-25 having the lowest rates of injury and those 36-45 having the highest rates. Claims rates were 1.36-fold higher for women than men. Women had higher rates for injury resulting from lifting, falling, noxious exposures, repetitive motion, and carpal tunnel syndrome. Similarly women had significantly higher rates of claims for pain, sprains, bruises, burns, concussion, and inhalation injury; with lower rates of cuts, ligament injury, and jammed joints. CONCLUSIONS: These group differences suggest the need to examine age and gender job distributions and relevant ergonomic and environmental causative factors.

Peripheral arterial embolism originating from a thrombus in the ascending aorta.

A 45-year-old man experienced arterial thromboembolism to the right leg requiring surgical restoration of blood flow. Transesophageal echocardiography (TEE) was performed to determine the source of embolism and identified a localized atherosclerotic lesion in the distal ascending aorta with an adherent, highly mobile thrombus. The patient underwent surgery with removal of the atherosclerotic plaque and attached thrombus, and resection of the adjacent aortic wall. This case illustrates an unusual location for a complex atherosclerotic lesion in the ascending aorta, and points out the opportunity for remedial surgery once a symptomatic embolus has occurred.

Thrombotic formations within the aortic arch as source of embolization in patients with coagulopathia.

Thrombotic formations on atherosclerotic lesions of the thoracic aorta are potential sources of cerebral and systemic embolization. Especially younger patients without calcifications of atherosclerotic plaques or coagulation disorders have a higher risk for embolization. Magnetic resonance imaging and transesophageal echocardiography are the diagnostic methods of choice. As an alternative to anticoagulation surgical therapy is indicated to prevent severe brain damage or multiorgan failure in patients with mobile thrombotic formations. Herein we describe two patients in whom successful surgical treatment was performed in deep hypothermic circulatory arrest by excision of the aortic arch atheroma.

Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning.

Although much has been learned about the neurobiological mechanisms underlying Pavlovian fear conditioning at the systems and cellular levels, relatively little is known about the molecular mechanisms underlying fear memory consolidation. The present experiments evaluated the role of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade in the amygdala during Pavlovian fear conditioning. We first show that ERK/MAPK is transiently activated-phosphorylated in the amygdala, specifically the lateral nucleus (LA), at 60 min, but not 15, 30, or 180 min, after conditioning, and that this activation is attributable to paired presentations of tone and shock rather than to nonassociative auditory stimulation, foot shock sensitization, or unpaired tone-shock presentations. We next show that infusions of U0126, an inhibitor of ERK/MAPK activation, aimed at the LA, dose-dependently impair long-term memory of Pavlovian fear conditioning but leaves short-term memory intact. Finally, we show that bath application of U0126 impairs long-term potentiation in the LA in vitro. Collectively, these results demonstrate that ERK/MAPK activation is necessary for both memory consolidation of Pavlovian fear conditioning and synaptic plasticity in the amygdala.

The effect of leukocyte-depleted blood cardioplegia in patients with severe left ventricular dysfunction: a randomized, double-blind study.

BACKGROUND: The propensity for leukocytes to cause reperfusion injury in patients undergoing heart surgery is widely accepted. Reperfusion injury may result in myocardial damage and unfavorable operative outcome, especially in patients with severely reduced ejection fractions. This study was performed to evaluate the impact of leukocyte filtration on the postoperative course of patients undergoing coronary bypass surgery. METHODS: Thirty-two patients with coronary artery disease and left ventricular ejection fraction less than 35% were included in this double-blind, randomized study. Two serial leukocyte removal filters (Pall BC1B filter [Pall Biomedical, Portsmouth, England], group F, 15 patients) or two dummy filters (group C, 17 patients) were connected to the blood cardioplegia line. Leukocyte count, hemodynamic measurement, and transesophageal echocardiography were performed before and after cardiopulmonary bypass. Cardiac-specific enzymes were analyzed from arterial blood during the first 72 hours and from coronary sinus blood 30 and 60 minutes after aortic unclamping. RESULTS: Patient characteristics were similar in the two groups (ejection fraction 20.9% +/- 4.3% in group C and 21.1% +/- 4.8% in group F; P =.773). No early death or perioperative myocardial infarction occurred. Leukocyte count, hemodynamic parameters, cardiac troponin T, cardiac troponin I, and creatine kinase MB mass levels in arterial blood were similar in the two groups. Group F showed lower release of cardiac troponin T from the coronary sinus 30 minutes after unclamping of the aorta (group F, 0.263 +/- 0.12 ng/mL; group C, 0.6 +/- 0.32 ng/mL; P =.005). Lower doses of dopamine were necessary after cardiopulmonary bypass (group F, 0.36 +/- 0.11 mg x kg(-1) x min(-1); group C, 0.49 +/- 0.14 mg x kg(-1) x min(-1); P =.003). A moderate increase in ejection fraction was observed at 30 minutes in both groups (group F, 30.3% +/- 6.2%; group C, 28.0% +/- 6.3%; P =.239) and a significant increase at 60 minutes in group F (group F, 32.5% +/- 6.0%; group C, 27.4% +/- 7.5%; P =.012). CONCLUSIONS: These results indicate that serial leukocyte filters connected to the blood cardioplegia line decrease myocardial cell injury and may therefore help to improve outcome of patients with severely depressed ejection fractions undergoing coronary artery bypass grafting.

[Symptomatic true aneurysm of a venous bypass with compression of the right atrium]. / Symptomatisches echtes Aneurysma eines Venenbypass mit Kompression des rechten Vorhofes.

A symptomatic true aneurysm of a saphenous vein graft to the right coronary artery in a female patient twelve years after bypass surgery is presented. Beating heart surgery included resection of the aneurysmatic saphenous vein graft, reconstruction of the right atrium and coronary artery bypass grafting to the right coronary artery. The symptoms of aneurysms of vein grafts, the diagnostic procedures and the surgical treatment are discussed.

Simvastatin attenuates vascular hypercoagulability in cardiac transplant recipients.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to reduce cardiac allograft failure and to lower the incidence of transplant coronary artery disease. These effects result from as yet unknown mechanisms not clearly attributable to lipid lowering. We here report that low-dose simvastatin treatment inhibits excessive expression of monocyte tissue factor (TF) and reduces the persistent hypercoagulability state seen in cardiac transplant recipients. METHODS: Fifteen consecutive heart transplant recipients receiving standard oral immunosuppression were newly assigned to a 10 mg daily simvastatin therapy. Levels of TF activity in both unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells drawn from transplant recipients before and under simvastatin therapy were evaluated by one-stage clotting assay. RESULTS: Monocyte TF activity was found to be significantly increased in cardiac transplant recipients when compared with healthy controls. Excessive monocyte procoagulant activity was reduced in cardiac transplant recipients during simvastatin treatment. This effect occurred independently of the reduction of serum low-density lipoprotein cholesterol. As demonstrated by reverse transcriptase-polymerase chain reaction, monocyte TF reduction by simvastatin, observed in 13 of the 15 transplant recipients investigated, could be ascribed to an inhibition of monocyte TF gene transcription. The reduction of monocyte TF activity during treatment with simvastatin paralleled with the normalization of elevated levels of thrombin-antithrombin complex, prothrombin fragment F1+2, and D-dimer, which are markers of thrombin and fibrin formation indicating coagulation activation after cardiac transplantation. CONCLUSION: Inhibition of monocyte TF expression and attenuation of the persistent hypercoagulable state observed in cardiac transplant recipients during treatment with simvastatin may represent an important mechanism by which HMG-CoA reductase inhibitors protect against the development of transplant coronary artery disease.

Do patients want minimally invasive aortic valve replacement?

OBJECTIVE: Access to aortic valve can be performed through small incisions. However, a considerable advantage of this approach has not been proven by randomized studies so far. We wanted to elucidate the opinion of patients when they are informed objectively about advantages and disadvantages of minimally invasive approach prior to operation. METHODS: This prospective study was performed with 27 patients undergoing isolated aortic valve replacement. These patients were informed prior to operation by the same resident concerning objective data. A photograph was shown illustrating a patient with postoperative wound after a standard- and a mini-incision, respectively. After the interview the patient could decide between full and partial sternotomy. RESULTS: After the interview 21/27 (78%) patients preferred to have a full sternotomy (group F) and 6/27 (22%) patients (group P) decided to have a partial sternotomy. Comments of group F: surgeon should have best exposure (n=15); cosmetics aspects unimportant (n=14); operation time as short as possible (n=7). Group P: cosmetic aspects important (n=6). Significant differences between groups (group F vs. group P): age (years), 69.1+/-1.5 vs. 49.2+/-7.3 (P=0.024); operation time (min), 142+/-7 vs. 189+/-15 (P=0.002); CK (IU/l), 111+/-11 vs. 374+/-114 (P=0.0007); CKMB (IU/l), 17+/-2 vs. 45+/-17 (P=0.006); ICU-stay (days), 2.6+/-0.2 vs. 3.2+/-0.2 (P=0.044). Pericardial effusion requiring drainage was observed in two patients of group P. One patient of group P suffered myocardial infarction. CONCLUSION: When patients are informed objectively about advantages and disadvantages of minimal invasive aortic valve surgery only a smaller number decides to have a mini incision. The patients preferring short incisions are significantly younger since cosmetic aspects are more important. Longer duration of operation may be due to longer hemostasis based on limited exposure. Air bubbles due to inadequate de-airing might be responsible for higher CK and CK-MB levels in group P.