Mice tune out not in: violation of prediction drives auditory saliency.

Successful navigation in complex acoustic scenes requires focusing on relevant sounds while ignoring irrelevant distractors. It has been argued that the ability to track stimulus statistics and generate predictions supports the choice of what to attend and what to ignore. However, the role of these predictions about future auditory events in drafting decisions remains elusive. While most psychophysical studies in humans indicate that expected stimuli are more easily detected, most work studying physiological auditory processing in animals highlights the detection of unexpected, surprising stimuli. Here, we tested whether in the mouse, high target probability results in enhanced detectability or whether detection is biased towards low-probability deviants using an auditory detection task. We implemented a probabilistic choice model to investigate whether a possible dependence on stimulus statistics arises from short-term serial correlations or from integration over longer periods. Our results demonstrate that target detectability in mice decreases with increasing probability, contrary to humans. We suggest that mice indeed track probability over a timescale of at least several minutes but do not use this information in the same way as humans do: instead of maximizing reward by focusing on high-probability targets, the saliency of a target is determined by surprise.

Stroke alters respiratory burst in neutrophils and monocytes.

BACKGROUND AND PURPOSE: Stroke-induced immune alterations predispose patients to infections. Although the relationship between stroke and the adaptive immune system has been investigated in detail, to date it is unknown whether the innate immune system, which forms the first line of antibacterial defense, is also impaired in patients with stroke. Therefore, we investigated whether chemotaxis, phagocytosis, oxidative burst, degranulation of defensins, and NETosis in monocytes and in neutrophil granulocytes are altered in patients with stroke compared with controls. METHODS: Sixty-three patients having acute ischemic stroke were recruited within 12 hours of symptom onset; blood was sampled on admission and on days 1, 3, 5, and 7. Thirty-seven age-matched controls were also recruited. Cell migration, phagocytosis, and oxidative burst of phagocytes were determined in vitro. Human neutrophil peptides 1 to 3 and serum metanephrine levels were measured by enzyme-linked immunosorbent assay, and NETosis was quantified by immunohistochemistry. RESULTS: The key mechanisms required for bacterial killing, oxidative burst, and NETosis were significantly reduced in samples taken from patients with stroke compared with controls, whereas migration, phagocytic function, and defensin production remained unimpaired in monocytes and granulocytes from patients with stroke. CONCLUSIONS: Stroke-induced immune alterations include impairment of the first-line defense performed by specialized phagocytes against bacteria. The hypothesis that these changes enhance susceptibility to acquired infections is supported by our observation that on admission oxidative burst in monocytes was more impaired in patients with stroke with subsequent stroke-associated infections.

Differential expression of matrix metalloproteases in human fibroblasts with different origins.

Fibroblasts are widely distributed cells and are responsible for the deposition of extracellular matrix (ECM) components but also secrete ECM-degrading matrix metalloproteases. A finely balanced equilibrium between deposition and degradation of ECM is essential for structural integrity of tissues. In the past, fibroblasts have typically been understood as a uniform cell population with comparable functions regardless of their origin. Here, we determined growth curves of fibroblasts derived from heart, skin, and lung and clearly show the lowest proliferation rate for cardiac fibroblasts. Furthermore, we examined basal expression levels of collagen and different MMPs in these three types of fibroblasts and compared these concerning their site of origin. Interestingly, we found major differences in basal mRNA expression especially for MMP1 and MMP3. Moreover, we treated fibroblasts with TNF-α and observed different alterations under these proinflammatory conditions. In conclusion, fibroblasts show different properties in proliferation and MMP expression regarding their originated tissue.

Increased left ventricular stiffness impairs exercise capacity in patients with heart failure symptoms despite normal left ventricular ejection fraction.

Aims. Several mechanisms can be involved in the development of exercise intolerance in patients with heart failure despite normal left ventricular ejection fraction (HFNEF) and may include impairment of left ventricular (LV) stiffness. We therefore investigated the influence of LV stiffness, determined by pressure-volume loop analysis obtained by conductance catheterization, on exercise capacity in HFNEF. Methods and Results. 27 HFNEF patients who showed LV diastolic dysfunction in pressure-volume (PV) loop analysis performed symptom-limited cardiopulmonary exercise testing (CPET) and were compared with 12 patients who did not show diastolic dysfunction in PV loop analysis. HFNEF patients revealed a lower peak performance (P = .046), breathing reserve (P = .006), and ventilation equivalent for carbon dioxide production at rest (P = .002). LV stiffness correlated with peak oxygen uptake (r = -0.636, P < .001), peak oxygen uptake at ventilatory threshold (r = -0.500, P = .009), and ventilation equivalent for carbon dioxide production at ventilatory threshold (r = 0.529, P = .005). Conclusions. CPET parameters such as peak oxygen uptake, peak oxygen uptake at ventilatory threshold, and ventilation equivalent for carbon dioxide production at ventilatory threshold correlate with LV stiffness. Increased LV stiffness impairs exercise capacity in HFNEF.

CT bronchoscopic simulation for guiding transbronchial needle aspiration of extramural mediastinal and hilar lesions: initial clinical results.

PURPOSE: To compare the yield of transbronchial needle aspiration (TBNA) with conventional orientation by using axial computed tomographic (CT) sections and that of TBNA with CT bronchoscopic simulation guidance for diagnosis of bronchoscopically occult extramural mediastinal and hilar lesions and the hit rates of both methods with regard to lesion number, size, and location in an intraindividual setting. MATERIALS AND METHODS: During this institutional review board-approved study, 28 patients with 50 bronchoscopically invisible lesions (mean short-axis diameter, 14 mm +/- 5 [standard deviation]; range, 6-38 mm) of the mediastinum and hilum gave informed consent and underwent TBNA. For CT bronchoscopic simulation, the target was displayed at virtual bronchoscopy to localize the best needle insertion point for TBNA. Each lesion was initially punctured with knowledge of axial CT sections only, followed by a second pass after reviewing CT bronchoscopic simulation. A hit was defined when specific material (eg, lymphatic or malignant cells) was obtained. Both methods were compared with respect to lesion size and location of successful punctures. RESULTS: With orientation by using CT bronchoscopic simulation, 29 of 50 lesions were successfully punctured, whereas only 15 lesions were hit with orientation by using axial CT sections (P < .05). Hit rate of CT bronchoscopic simulation was superior to conventional orientation independent of lesion size and location. CONCLUSION: Orientation by using CT bronchoscopic simulation helps improve guidance for TBNA of bronchoscopically invisible lesions of the mediastinum and the hilum, increases the hit rate, and may be a helpful tool for less experienced bronchoscopists. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/250/3/923/DC1.

Tissue factor expression pattern in human non-small cell lung cancer tissues indicate increased blood thrombogenicity and tumor metastasis.

Non-small cell lung cancer (NSCLC) comprises of 75% of all lung cancers. Human full length tissue factor (flHTF), the physiological initiator of blood coagulation, is aberrantly expressed in certain solid tumors. FlHTF and its soluble isoform, alternatively spliced human tissue factor (asHTF), have been shown to contribute to thrombogenicity of the blood of healthy individuals. The aim of this study was to quantify flHTF and asHTF on mRNA and protein levels (using immunohistochemistry, immunoblotting, and ELISA) on a panel of human NSCLC tissue and plasma specimens. The tissue factor (TF) expression of 21 pulmonary adenomatous (AC) and 12 normal healthy tissues was assessed by real-time qRT-PCR. The TF protein concentration was quantified by ELISA in a subset of 11 AC and 9 normal tissue specimens as well as in the plasma of 13 lung cancer patients and 15 healthy controls. We found a significant increase in the ratio of flHTF/HGAPDH mRNA in AC (0.24+/-0.06 vs. 0.07+/-0.01; p=0.02 vs. controls) and in asHTF/HGAPDH mRNA (0.027+/-0.01 vs. 0.004+/-0.001; p=0.03 AC vs. controls). AsHTF mRNA expression was significantly lower in patients with stage IA disease compared to patients with higher grade stages, pointing to TF as being a marker of malignancy and metastases. TF protein of lung tumors was significantly increased in AC (p=0.004 vs. controls). TF in plasma was up-regulated in lung cancer patients (334.9+/-95.4 vs. 124.1+/-14.8 pg/ml; p=0.02 vs. controls). Immunohistochemical and immunoblotting data are in line with the increased TF expression, showing elevated blood thrombogenicity of NSCLC patients. The up-regulation of flHTF and, especially, asHTF in AC suggests not only a raised risk of thrombosis, but also of tumor progression, thereby, indicating a poor prognosis in these patients.

Computed tomography-bronchoscopic simulation for guiding transbronchial fine needle aspiration of extramural targets: a phantom study.

OBJECTIVES: Extramural paratracheal/-bronchial tumors of the mediastinum and the hilum that cannot be seen in bronchoscopy constitute a particular challenge for transbronchial fine needle aspiration cytology. A software prototype was developed as a guidance tool to visualize extramural targets on computed tomography (CT)-bronchoscopy. A phantom study was conducted to evaluate this guidance tool. MATERIAL AND METHODS: For CT-bronchoscopic simulation extramural targets are visualized behind the semitransparent wall in the endoluminal view. An airway phantom with 16 targets was examined by 3 bronchoscopists. In a first pass the targets were bronchoscopically punctured in the conventional way only with knowledge of axial CT-sections. In a second pass guidance by CT-bronchoscopic simulation was used. A postinterventional CT scan of the phantom was conducted to analyze the spatial relationship between the marked puncture sites and the targets. The punctures were classified in hits and failed punctures due to deviation in distance and angle. RESULTS: The total hit rate of the 3 operators was significantly higher with CT-bronchoscopic simulation (32 of 48) than with the conventional method (14 of 48; P < 0.01). Concerning the failed punctures the deviation in distance and angle was significantly smaller with CT-bronchoscopic simulation (P < 0.01, P < 0.05, respectively). CONCLUSION: CT-bronchoscopic simulation significantly increased hit rate of bronchoscopic punctures of extramural lesions compared with conventional orientation using axial CT-sections in this phantom study. These results suggest that CT-bronchoscopic simulation might be a valuable tool for increasing yield and accuracy of bronchoscopic transbronchial fine needle aspiration in patients with mediastinal and hilar masses that are invisible for conventional bronchoscopy.

Adenosine enhances cytosolic phosphorylation potential and ventricular contractility in stunned guinea pig heart: receptor-mediated and metabolic protection.

Mechanisms of adenosine (ADO) protection of reperfused myocardium are not fully understood. We tested the hypothesis that ADO (0.1 mM) alleviates ventricular stunning by ADO A(1)-receptor stimulation combined with purine metabolic enhancements. Langendorff guinea pig hearts were stunned at constant left ventricular end-diastolic pressure by low-flow ischemia. Myocardial phosphate metabolites were measured by (31)P-NMR, with phosphorylation potential {[ATP]/([ADP].[P(i)]), where brackets indicate concentration} estimated from creatine kinase equilibrium. Creatine and IMP, glycolytic intermediates, were measured enzymatically and glycolytic flux and extracellular spaces were measured by radiotracers. All treatment interventions started after a 10-min normoxic stabilization period. At 30 min reperfusion, ventricular contractility (dP/dt, left ventricular pressure) was reduced 17-26%, ventricular power (rate-pressure product) by 37%, and [ATP]/([ADP].[P(i)]) by 53%. The selective A(1) agonist 2-chloro-N(6)-cyclo-pentyladenosine marginally preserved [ATP]/([ADP].[P(i)]) and ventricular contractility but not rate-pressure product. Purine salvage precursor inosine (0.1 mM) substantially raised [ATP]/([ADP].[P(i)]) but weakly affected contractility. The ATP-sensitive potassium channel blocker glibenclamide (50 microM) abolished ADO protection of [ATP]/([ADP].[P(i)]) and contractility. ADO raised myocardial IMP and glucose-6-phosphate, demonstrating increased purine salvage and pentose phosphate pathway flux potential. Coronary hyperemia alone (papaverine) was not cardioprotective. We found that ADO protected energy metabolism and contractility in stunned myocardium more effectively than both the A(1)-receptor agonist 2-chloro-N(6)-cyclo-pentyladenosine and the purine salvage precursor inosine. Because ADO failed to stimulate glycolytic flux, the enhancement of reperfusion, [ATP]/([ADP].[P(i)]), indicates protection of mitochondrial function. Reduced ventricular dysfunction at enhanced [ATP]/([ADP].[P(i)]) argues against opening of mitochondrial ATP-sensitive potassium channel. The results establish a multifactorial mechanism of ADO antistunning, which appears to combine ADO A(1)-receptor signaling with metabolic adenylate and antioxidant enhancements.

Phase II trial of second-line bendamustine chemotherapy in relapsed small cell lung cancer patients.

PURPOSE: The efficacy and toxicity of bendamustine chemotherapy in relapsed small cell lung cancer (SCLC) was determined in this phase II trial. PATIENTS AND METHODS: Patients with cytologically or histologically proven SCLC, who had a sensitive relapse, which was defined as a relapse>or=2 months after completion of primary therapy, were eligible for this study. After informed consent patients received 120 mg/m2 of bendamustine on Days 1 and 2 every 3 weeks. A maximum of six cycles was administered. Primary endpoint was response rate, secondary endpoints included toxicity, progression free survival and overall survival (OS). RESULTS: Twenty-one patients with a median age of 59 years (range 47-76) were accrued to this trial. Six (29%) of 21 patients achieved a confirmed partial remission, 6 (29%) had stable disease and 9 (42%) patients progressed according to RECIST criteria. Median progression free survival was 4 months (95% CI 0-8, 3), median overall survival was 7 months (95% CI 5, 8-8, 2). One- and 2-year survival was 16% and 8%, respectively. Grade III/IV neutropenia occurred in 3 (15%) of 21 patients, 1 patient had a lethal Gram-negative sepsis in neutropenia. Two additional patients had pneumonia in the absence of neutropenia. Two patients (10%) had a grade III anemia, no grade III or IV thrombocytopenia was observed. CONCLUSION: This trial demonstrates efficacy of bendamustine in relapsed SCLC and a favourable toxicity profile. Therefore, single-agent bendamustine is a treatment option for patients with SCLC, who have responded to initial platinum containing chemotherapy and should further be investigated in randomized trials.

Phase II trial of carboplatin, paclitaxel plus vinorelbine in non-small cell lung cancer patients.

BACKGROUND: Vinorelbine was added to carboplatin plus paclitaxel to determine efficacy and toxicity in non-small cell lung cancer (NSCLC) patients with good performance status. PATIENTS AND METHODS: Vinorelbine 30 mg/m2 plus paclitaxel 175 mg/m2 plus carboplatin AUC 5 was administered every three weeks for a maximum of 6 cycles. RESULTS: One out of 37 patients had a complete and 12 a partial remission (35% response rate). Six patients (16%) had disease stabilization and 18 (49%) progressed. Grade III or IV neutropenia occurred in 11 (30%) and febrile neutropenia in 6 (16%) patients. Grade III/IV neuropathy was observed in 6 (16%) patients. The median time to progression was 6 months (95% CI 4.0 - 8.0), and median survival 11 months (95% CI 8.3 - 13.7). One- and two-year survival was 41% (95% CI 24 - 58) and 24% (95% CI 8.7 - 39.1), respectively. CONCLUSION: This triple-chemotherapy combination is feasible. The response rates justify further investigation in similar patient subgroups.

Angiotensin deficiency in mice leads to dilated cardiomyopathy.

To explore the role of angiotensin II, we assessed hemodynamics and cardiac function in angiotensinogen-deficient mice in comparison to wild-type animals. Left ventricular end-diastolic diameter and wall thickness were evaluated by echocardiography and systolic and diastolic left ventricular function by pressure-volume relations using a micro-conductance catheter. Compared to wild-type animals, the angiotensinogen-deficient mice were hypotensive and showed impaired systolic function. The hearts were dilated, demonstrated by echocardiography and by a right-ward shift of the pressure-volume loops, but end-diastolic pressure, isovolumic relaxation (tau) and diastolic stiffness were unchanged. Afterload, however, was reduced leading to maintained cardiac output. Although a blockade of the renin-angiotensin system via angiotensin converting enzyme inhibitors or angiotensin AT1 receptor antagonist is beneficial after cardiac failure, the absence of angiotensin peptides during the ontogenesis leads to dilated cardiomyopathy.

The humoral immune response in viral heart disease: characterization and pathophysiological significance of antibodies.

Several lines of evidence suggest a viral infection as the initiating event for the development of myocarditis (MC). Especially enteroviruses like coxsackie B3 virus have been shown to induce MC in humans and strains of MC-prone mice after an infection. The further course of the disease is, however, determined not only by the viral infection but also by the host's immune system. Both the humoral and the cellular immune system can modify the extent of the damage caused by the disease. The humoral immune system mounts an anti-viral immune response immediately after the infection; however, during the course of the disease, autoantibodies against a variety of different autoantigens emerge. The epitopes recognized by the anti-viral antibodies and those of several autoantibodies have been identified using synthetic peptides. The human disease could be transferred into SCID mice using peripheral blood leukocytes of patients, suggesting a pathophysiological significance of the autoimmune reaction. However, the significance of the humoral immune responses needs to be tested in randomized, prospective studies using immunoadsorption of autoantibodies in patients with inflammatory cardiomyopathy.

Cardiac kinin level in experimental diabetes mellitus: role of kininases.

Diabetes mellitus impairs the cardiac kallikrein-kinin system by reducing cardiac kallikrein (KLK) and kininogen levels, a mechanism that may contribute to the deleterious outcome of cardiac ischemia in this disease. We studied left ventricular (LV) function and bradykinin (BK) coronary outflow in buffer-perfused, isolated working hearts (n = 7) of controls and streptozotocin (STZ)-induced diabetic rats before and after global ischemia. With the use of selective kininase inhibitors, the activities of angiotensin I-converting enzyme, aminopeptidase P, and neutral endopeptidase were determined by analyzing the degradation kinetics of exogenously administered BK during sequential coronary passages. Basal LV function and coronary flow were impaired in STZ-induced diabetic rats. Neither basal nor postischemic coronary BK outflow differed between control and diabetic hearts. Reperfusion after 15 min of ischemia induced a peak in coronary BK outflow that was of the same extent and duration in both groups. In diabetic hearts, total cardiac kininase activity was reduced by 41.4% with an unchanged relative kininase contribution compared with controls. In conclusion, despite reduced cardiac KLK synthesis, STZ-induced diabetic hearts are able to maintain kinin liberation under basal and ischemic conditions because of a primary impairment or a secondary downregulation of kinin-degrading enzymes.