Soluble Adhesion Molecules During Ex Vivo Lung Perfusion Are Associated With Posttransplant Primary Graft Dysfunction.

Ex vivo lung perfusion (EVLP) enables assessment of marginal donor lungs for transplantation. We aimed to discover biomarkers in EVLP perfusate that could predict development of primary graft dysfunction (PGD). From September 2008 to August 2013, 100 clinical EVLPs were performed. Eleven patients developed PGD grade 3 within 72 h after transplant. The non-PGD group consisted of 34 patients without PGD grade 3. Nonbilateral lung transplants or transplant after extracorporeal life support were excluded from analyses. Soluble intercellular adhesion molecule 1 (sICAM-1), soluble VCAM-1 (sVCAM-1), and soluble E selectin (sE-selectin) levels, as markers of endothelial activation, were measured in the perfusate of EVLP by enzyme-linked immunosorbent assay and were correlated with clinical outcome. Levels of sICAM-1 at 1 h and sVCAM-1 at 1 and 4 h were significantly higher in the PGD group compared with the non-PGD group. The sE selectin levels were not statistically different between the study groups. Higher levels of sVCAM-1 at 1 and 4 h were statistically significantly associated with PGD either alone or after adjustment for other PGD risk factors. These adhesion molecules may help identify donor lungs at higher risk of PGD during EVLP.

Pioglitazone prevents smoking carcinogen-induced lung tumor development in mice.

Pioglitazone (PGZ), a synthetic peroxisome proliferator-activated receptor gamma (PPARγ) ligand, is known to have anti-tumor activity by inducing tumor cell apoptosis. However, it is unknown whether it can be used to prevent smoking carcinogen-induced lung tumor development. We induced mouse lung tumors using smoking carcinogen 4- methylnitrosamino-l-3-pyridyl-butanone (NNK). PGZ was given at two early stages before the tumor formation. The role and the functional mechanism of PGZ were investigated in the development of mouse pulmonary tumors. The tumor development was monitored and PPARγ activity and endogenous PPARγ ligands 15(S)-HETE, 13(S)-HODE were determined. The application of PGZ before alveolar hyperplasia formation (Group NPa) and at the early phase of alveolar hyperplasia formation (Group NPb) significantly prevented the lung tumor development especially in Group NPb mice (all p < 0.05). PGZ not only prevented the NNK-mediated reduction of endogenous ligands 15(S)-HETE and 13(S)-HODE, but also increased 13(S)-HODE level in Group NPb mice. PPARγ transcriptional activity was increased in NNKstimulated lung tissues when PGZ was given. The in vivo results were confirmed in the human lung cancer cells, which showed that PGZ induced lung cancer cell apoptosis through up-regulating nuclear PPARγ expression, inducing PPARγ transcriptional activity and increasing the levels of PPARγ ligands in NNK-treated cells. The early application of PGZ is able to prevent NNK-induced lung tumor development through maintaining the level of endogenous PPARγ ligands 15(S)-HETE and 13(S)-HODE and activation of PPARγ.

4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor.

The role of thromboxane A(2) (TxA(2)) in smoking-associated lung cancer is poorly understood. This study was conducted to study the role of TxA(2) in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells. We found that NNK increased TxA(2) synthase (TxAS) expression and thromboxane B(2) (TxB(2)) generation in cultured lung cancer cells, the result of which was supported by the increased level of TxAS in lung cancer tissues of smokers. Both TxAS-specific inhibitor furegrelate and TxA(2) receptor antagonist SQ29548 completely blocked NNK-mediated cell survival and growth via inducting apoptosis. TxA(2) receptor agonist U46619 reconstituted a near-full survival and growth response to NNK when TxAS was inhibited, affirming the role of TxA(2) receptor in NNK-mediated cell survival and growth. Suppression of cyclic adenosine monophosphate response element binding protein (CREB) activity by its small interference RNA blocked the effect of NNK. Phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) also had a positive role. Altogether, our results have revealed that NNK stimulates TxA(2) synthesis and activates its receptor in lung cancer cells. The increased TxA(2) may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells.

Resolution enhancement of imaging small-scale portions in a compactly supported function.

The ambiguity involved in reconstructing an image from limited Fourier data is removed using a new technique that incorporates prior knowledge of the location of regions containing small-scale features of interest. The prior discrete Fourier transform (PDFT) method for image reconstruction incorporates prior knowledge of the support, and perhaps general shape, of the object function being reconstructed through the use of a weight function. The new approach extends the PDFT by allowing different weight functions to modulate the different spatial frequency components of the reconstructed image. The effectiveness of the new method is tested on one- and two-dimensional simulations.

Resolution enhancement in computerized tomographic imaging.

We consider the problem of reconstructing an object function f(r) from finitely many linear functional values. In our main application, the function f(r) is a tomographic image, and the data are integrals of f(r) along thin strips. Because the data are limited, resolution can be enhanced through the inclusion of prior knowledge. One way to do that, a generalization of the prior discrete Fourier transform (PDFT) method, was suggested in 1982 [SIAM J. Appl. Math.42,933 (1982)] but was found to be difficult to implement for the tomography problem, and that application was not pursued. Recent advances in approximating the PDFT make it possible to achieve the desired resolution enhancement in an easily implemented procedure.

Haem oxygenase-1 plays a central role in NNK-mediated lung carcinogenesis.

The tobacco-specific nitrosamine, 4-(N-methyl-N-nitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent lung cancer inducer. However, how NNK induces lung cancer is still largely unknown. Haem oxygenase (HO)-1 was evaluated in 30 pairs of lung cancer tumour samples and matched nontumour tissues from patients with a history of cigarette smoking. Expression of HO-1, p21(Cip1/Waf1/Cid1) (p21), B-cell lymphoma (Bcl)-2 family members, mitogen-activated protein kinase and nuclear factor (NF)-kappaB was also studied in lung cancer cells treated with NNK. The levels of HO-1 and p21 were significantly increased in lung tumour tissues. There was a positive relationship between these two proteins in the tumour. NNK stimulated lung cell proliferation and elevated the levels of HO-1, p21, inhibitor of apoptosis protein (c-IAP)2 and Bcl-2, but downregulated Bad. These effects of NNK were blocked by zinc protoporphyrin-XII, an HO-1 inhibitor. The NNK-mediated expression of HO-1 was governed by NF-kappaB and extracellular signal-regulated kinase 1/2, since blocking either of these prevented the stimulatory effect of NNK on HO-1, as well as molecules downstream of HO-1, such as p21, c-IAP2, Bcl-2 and Bad. In conclusion, haem oxygenase-1 plays a central role in NNK-mediated cell proliferation by promoting the expression of p21(Cip1/Waf1/Cid1), inhibitor of apoptosis protein 2 and B-cell lymphoma-2 but inhibiting the activity of Bad. Nuclear factor-kappaB and extracellular signal-regulated kinase 1/2 function upstream of haem oxygenase-1. Therefore, haem oxygenase-1 is likely to be a potential target in the treatment of smoking-related lung cancer.

Image reconstruction from limited Fourier data.

We consider the problem of reconstructing a function f with bounded support S from finitely many values of its Fourier transform F. Although f cannot be band limited since it has bounded support, it is typically the case that f can be modeled as the restriction to S of a sigma-band-limited function, say g. Our reconstruction method is based on such a model for f. Of particular interest is the effect of the choice of sigma > 0 on the resolution.

Accuracy of extrapolated data as a function of prior knowledge and regularization.

The prior discrete Fourier transform (PDFT) is a linear spectral estimator that provides a solution that is both data consistent and of minimum weighted norm through the use of a suitably designed Hilbert space. The PDFT has been successfully used in imaging applications to improve resolution and overcome the nonuniqueness associated with having only finitely many spectral measurements. With the use of an appropriate prior function, the resolution of the reconstructed image can be improved dramatically. We explore the ways in which some significant parameters affect the PDFT estimate. A relationship between estimated spectral values, prior knowledge, and regularization was examined. It allows one to assess the reliability of the estimated spectral values for a given choice of prior estimate and provides a means for optimizing PDFT-based estimators.

Iterative image reconstruction using prior knowledge.

A method is proposed to reconstruct signals from incomplete data. The method, which can be interpreted both as a discrete implementation of the so-called prior discrete Fourier transform (PDFT) spectral estimation technique and as a variant of the algebraic reconstruction technique, allows one to incorporate prior information about the reconstructed signal to improve the resolution of the signal estimated. The context of diffraction tomography and image reconstruction from samples of the far-field scattering amplitude are used to explore the performance of the method. On the basis of numerical computations, the optimum choice of parameters is determined empirically by comparing image reconstructions of the noniterative PDFT algorithm and the proposed iterative scheme.

Image reconstruction: a unifying model for resolution enhancement and data extrapolation. Tutorial.

In reconstructing an object function F(r) from finitely many noisy linear-functional values integral of F(r)Gn(r)dr we face the problem that finite data, noisy or not, are insufficient to specify F(r) uniquely. Estimates based on the finite data may succeed in recovering broad features of F(r), but may fail to resolve important detail. Linear and nonlinear, model-based data extrapolation procedures can be used to improve resolution, but at the cost of sensitivity to noise. To estimate linear-functional values of F(r) that have not been measured from those that have been, we need to employ prior information about the object F(r), such as support information or, more generally, estimates of the overall profile of F(r). One way to do this is through minimum-weighted-norm (MWN) estimation, with the prior information used to determine the weights. The MWN approach extends the Gerchberg-Papoulis band-limited extrapolation method and is closely related to matched-filter linear detection, the approximation of the Wiener filter, and to iterative Shannon-entropy-maximization algorithms. Non-linear versions of the MWN method extend the noniterative, Burg, maximum-entropy spectral-estimation procedure.

Modified Glenn connection for acutely ischemic right ventricular failure reverses secondary left ventricular dysfunction.

BACKGROUND: Right heart failure after cardiopulmonary bypass can result in severe hemodynamic compromise with high mortality, but the underlying mechanisms remain poorly understood. After ischemia-induced right ventricular failure, alterations in the interventricular septal position decrease left ventricular compliance and limit filling but may also distort left ventricular geometry and compromise contractility and relaxation. This study investigated the effect of acute isolated right ventricular ischemia on biventricular performance and interaction and the response of subsequent right ventricular unloading by use of a modified Glenn shunt. METHODS: In 8 pigs isolated right ventricular ischemic failure was induced by means of selective coronary ligation. A modified Glenn circuit was then established by a superior vena cava-pulmonary artery connection. Ventricular performance was determined by conductance catheter-derived right ventricular pressure-volume loops and left ventricular pressure-segment length loops. Hemodynamic data at baseline, after right ventricular ischemia, and after institution of the Glenn circuit were obtained during inflow occlusion, and the load-independent contractile indices were derived. RESULTS: Right ventricular free-wall ischemia resulted in acute right ventricular dilation (118 +/- 81 mL vs 169 +/- 70 mL, P =.0008) and impairment of left ventricular contractility indicated by the reduced end-systolic pressure-volume relation slope (50.0 +/- 19 mm Hg/mm vs 18.9 +/- 8 mm Hg/mm, P =.002) and preload recruitable stroke work index slope (69.6 +/- 26 erg x cm(-3) x 10(3) vs 39.7 +/- 13 erg x cm(-3) x 10(3), P =.003). In addition, left ventricular relaxation (tau) was significantly prolonged (33.3 +/- 10 ms vs 53.0 +/- 16 ms, P =.012). Right ventricular unloading with the Glenn shunt reduced right ventricular dilation and significantly improved left ventricular contraction, end-systolic pressure-volume relation slope (18.9 +/- 8 mm Hg/mm vs 35.8 +/- 18 mm Hg/mm, P =.002), preload recruitable stroke work index slope (39.7 +/- 26 erg x cm(-3) x 10(3) vs 63.0 +/- 22 erg x cm(-3) x 10(3), P =.003), and diastolic performance (tau 53.0 +/- 16 ms vs 43.5 +/- 13 ms, P =.001). CONCLUSIONS: Right ventricular ischemia-induced dilation resulted in acute impairment of left ventricular contractility and relaxation. A modified Glenn shunt attenuated the left ventricular dysfunction by limiting right ventricular dilation and restoring left ventricular cavity geometry.

Minimally invasive direct access heart valve surgery.

We review our experience with minimally invasive direct access (MIDA) heart valve surgery in 518 patients. Two hundred fifty-two patients underwent MIDA aortic valve replacement (AVR) or repair and 266 underwent MIDA mitral valve repair or replacement. Among the 250 AVRs, 157 (63%) were men, aged 63.2 +/- 14.6 years, NYHA functional Class 2.4 +/- 0.8. The surgical approach was right parasternal in 36 (14%) or upper hemisternotomy in 216 (86%). There were four (2%) operative deaths. Perioperative complications included 14 (5.6%) reexplorations for bleeding, 7 (3%) chest wound infections, 5 (2%) strokes, and 1 (0.4%) external iliac vein injury. Follow-up was complete in 193 (77%) patients, with a mean follow-up of 12 +/- 8 months. Late complications included 2 (0.8%) nonfatal myocardial infarctions, 4 (2%) reoperations for, respectively, 2 pericardial complications, 1 paravalvar leak, and 1 infected valve. There were five (2%) late deaths from congestive heart failure, pneumonia, hemorrhage, aneurysm, and cancer. Mean follow-up NYHA Class was 1.4 +/- 0.6. For the 266 mitral patients, 145 (54.5%) were men, age 58.7 +/- 13.6 years, functional Class 2.3 +/- 0.5. The surgical approach was right parasternal in 195 (73%), lower hemisternotomy in 53 (20%), right submammary thoracotomy in 9 (3.4%), or full sternotomy through a small skin incision in 9 (3.4%). There were 2 (0.8%) operative deaths. Perioperative complications included 4 (1.5%) reoperations for bleeding, 4 (1.5%) strokes, and 5 (2%) wound infections, and 3 (1%) ascending aortic complications. Follow-up was complete in 202 (76%) patients with a mean follow-up of 9.5 +/- 6.4 months. Late complications included one (0.4%) nonfatal myocardial infarction and three (1%) reoperations all converting repairs to replacements. There were three (1%) late deaths from suicide, pneumonia, and sudden death, respectively. Mean follow-up NYHA functional Class was 1.3 +/- 0.5. We conclude that MIDA heart valve surgery is safe and effective for the majority of patients requiring isolated elective aortic or mitral valve surgery.

Recurrent left cervical abscess secondary to persistent pyriform sinus fistula.

Congenital pyriform sinus fistula is a rare defect arising from the failure of obliteration of the third or fourth pharyngeal pouch remnant. It is a recognized potential cause of acute suppurative thyroiditis.

Anticoagulant control in the first three months after mechanical heart valve replacement.

To establish the precision of anticoagulant control in the first three months after mechanical heart valve replacement, 53 patients from a consecutive series of 91 were telephoned and asked to read out their anticoagulation record. The levels of international normalised ratio (INR) were analysed by Rosendaal's method. Twenty-nine per cent of patient days were spent with an INR in the recommended range of 3.0-4.5. Warfarin dosage was increased at a median INR of 2.1 (interquartile range 1.7-2.3), unchanged at 2.7 (interquartile range 2.3-3.1) and decreased at 4.3 (interquartile range 3.6-5.1). Anticoagulant control is poor in the first three months after mechanical heart valve replacement. Data on the INR at which warfarin dosage is changed suggest either that recommended guidelines are not being followed or a reluctance to increase the dosage in patients receiving inadequate anticoagulation.

Giant pericardial cysts.

Pericardial cysts are most commonly incidental radiologic findings of little clinical consequence. We present the unusual history of 2 patients in whom pericardial cysts were of massive sizes and caused significant symptoms; in 1, progression of the cyst size had been documented over 25 years. Diagnostic difficulties encountered and the utility of video-assisted thoracoscopy are described.