Fluorinated aldosterone synthase (CYP11B2)-inhibitors for differential diagnosis between bilateral and unilateral conditions of primary aldosteronism.

The enzyme aldosterone synthase (CYP11B2) is specifically expressed in aldosterone-producing tissue of the adrenal cortex and is overexpressed in aldosterone-producing adenomas (APA). It therefore represents an ideal target for molecular imaging, particularly for the differential diagnosis between bilateral hyperplasia and unilateral APA in primary aldosteronism. However, the presence of the cortisol-producing enzyme 11ß-hydroxylase (CYP11B1) in the adrenal cortex remains very challenging owing to its high homology to CYP11B2. Within this study, we efficiently synthesized a variety of disubstituted fluorinated pyridines and pyrazines by Suzuki coupling reactions. These compounds were evaluated for their ability to inhibit CYP11B1 and CYP11B2 in transfected Y1 cells and in NCI-h295 cells. Several compounds were found to exhibit excellent affinity (IC50 < 10 nM) to CYP11B2 as well as strong selectivity (up to 125-fold) over CYP11B1. These findings support the further development of an analogous 18F-labelled PET tracer.

Endothelin-1 inhibits background two-pore domain channel TASK-1 in primary human pulmonary artery smooth muscle cells.

Endothelin (ET)-1 causes long-lasting vasoconstriction and vascular remodeling by interacting with specific G-protein-coupled receptors in pulmonary artery smooth muscle cells (PASMCs), and thus plays an important role in the pathophysiology of pulmonary arterial hypertension. The two-pore domain K(+) channel, TASK-1, controls the resting membrane potential in human PASMCs (hPASMCs), and renders these cells sensitive to a variety of vasoactive factors, as previously shown. ET-1 may exert its vasoconstrictive effects in part by targeting TASK-1. To clarify this, we analyzed the ET-1 signaling pathway related to TASK-1 in primary hPASMCs. We employed the whole-cell patch-clamp technique combined with TASK-1 small interfering RNA (siRNA) in hPASMC and the isolated, perfused, and ventilated mouse lung model. We found that ET-1 depolarized primary hPASMCs by phosphorylating TASK-1 at clinically relevant concentrations. The ET sensitivity of TASK-1 required ET(A) receptors, phospholipase C, phosphatidylinositol 4,5-biphosphate, diacylglycerol, and protein kinase C in primary hPASMCs. The ET-1 effect on membrane potential and TASK-1 was abrogated using TASK-1 siRNA. This is the first time that the background K(+) channel, TASK-1, has been identified in the ET-1-mediated depolarization in native hPASMC, and might represent a novel pathologic mechanism related to pulmonary arterial hypertension.

Self-expandable covered metal tracheal type stent for sealing cervical anastomotic leak after esophagectomy and gastric pull-up: pitfalls and possibilities.

From January 2003 to June 2006, 6 patients with leakage of the cervical esophagogastrostomy after esophagectomy and gastric pull-up underwent endoscopic stenting using the self-expandable covered tracheal type device. Anastomotic healing was satisfactory. Stent extraction was performed after an average interval of 91 days. Initial stent migration occurred in 2 patients and post-extraction stenosis developed in 3 patients. Insertion of a self-expandable covered metal tracheal stent represents a safe approach resulting in immediate closure and subsequent healing of cervical anastomotic leakage.

A simplified technique for implantation of left ventricular epicardial leads for biventricular re-synchronization using video-assisted thoracoscopy (VATS).

OBJECTIVE: Cardiac re-synchronization therapy for treatment of heart failure requires transvenous insertion of both a right ventricular and left ventricular pacing lead. Implantation of the latter by way of the coronary sinus often fails. Therefore, alternative techniques for insertion are required. We applied a simple video-assisted surgical technique (VATS) using only two ports for the insertion of left-ventricular screw-in electrodes. METHODS: Fifteen patients (M: 10; F: 5; mean age: 62.2 years; range: 46-76 years) with heart failure meeting the ACC/AHA guidelines for implantation of biventricular pacing underwent transvenous insertion of the right atrial sensor lead and the right ventricular pacing lead. In all of them transvenous implantation of the left ventricular pacing lead failed, and they were planned for VATS. In right-lateral decubitus position and under single-lung ventilation a camera port and a flexible instrumentation port were inserted in the forth intercostal space. By using routine instruments, a T-shaped incision was made lateral to the phrenic nerve and an electrode was screwed in. The lead was guided subcutaneously to the pacemaker. RESULTS: Mean skin-to-skin operating time was 55+/-16 min, no conversion to thoracotomy was necessary. All patients were extubated in the operating room and remained in the intensive care unit for less than 24h. Chest tubes were removed after a mean of 1.6+/-0.5 days and the patients were discharged after a mean of 4+/-1.3 days. Intraoperative and postoperative pacing thresholds at 1 and 7 months were satisfactory in all cases and there was no lead dislocation. All but two patients had an improvement of their NYHA function class. There was neither surgical morbidity nor mortality. CONCLUSIONS: Video-assisted thoracoscopy over two ports seems to be an excellent alternative procedure for epicardial lead implantation. It is readily available and produces good pacing results at a short intervention time and tolerable stress for the patients.

Tension pneumomediastinum after severe vomiting in a 21-year-old female.

A 21-year-old female with chronic membranoproliferative nephritis was admitted for suspected esophageal disruption and asthma after severe, prolonged vomiting. At the time of admission she presented with dyspnea, tachypnea, arterial hypotension and tachycardia. Physical examination showed discrete signs of ectopic air at the neck and distended cervical veins. CT-scan of the chest showed severe mediastinal emphysema with compression of the right atrium. After cervical mediastinotomy the cardiorespiratory parameters normalized immediately. Esophagoscopy showed multiple longitudinal mucosal tears between 25 and 45 cm; fluoroscopically, there was no leakage of contrast medium. Following conservative treatment the patient recovered completely and was discharged on day 8.

Protein expression profiles in adenocarcinomas and squamous cell carcinomas of the lung generated using tissue microarrays.

With the appearance of defect-targeted therapies, the definition of tumour protein expression profiles has gained increasing importance. Two lung carcinoma tissue microarrays, one including 75 primary adenocarcinomas (ACs) and the other comprising 67 primary squamous cell carcinomas (SQCCs), were generated in the present study. On both arrays, each tumour was represented by an average of five cores. In addition, one punch of normal lung parenchyma adjacent to each tumour was included in the array. Immunohistochemical expression of 86 proteins was evaluated and the results were analysed by non-parametric tests, hierarchical clustering, and principal component analysis. In both tumour entities, parenchyma and tumours were clearly separated by hierarchical clustering. By the same statistical approach, it was possible to distinguish ACs from SQCCs with 98% accuracy and to distinguish parenchyma adjacent to ACs from that adjacent to SQCCs with 96% accuracy. It was also possible to separate ACs into three groups that significantly differed in survival. Cathepsin E and hsp105 were identified as previously unknown predictors of survival in lung AC. In summary, this study has shown that protein profiles are feasible tools for anticipating biological behaviour.

Severe heart laceration in penetrating chest trauma: thoracoscopy as a key to diagnosis.

A patient had attempted suicide by firing a butcher's gun into his left chest 3 cm caudal to the mammilla. Transthoracic echocardiography and CT-scan showed a discrete hematopneumothorax but no pericardial effusion, the cardio respiratory condition was stable. As the bolt had been aimed directly at the heart of the patient, thoracoscopy was performed to rule out cardiac trauma. Thoracoscopy showed a distinct severe contusion of the otherwise intact pericardium and a hemopericardium. Immediate thoracotomy and pericardiotomy revealed significant intrapericardial bleeding caused by an incomplete rupture of the left ventricle. The condition was successfully treated by direct reinforced suture.

Fractionated intraluminal HDR 192Ir brachytherapy as palliative treatment in patients with endobronchial metastases from non-bronchogenic primaries.

AIM: To evaluate the efficacy of iridium-192 high-dose rate (HDR) endobronchial brachytherapy for the palliation of symptoms caused by endobronchial metastases of non-bronchogenic primaries. PATIENTS AND METHOD: Between 1991 and 1998, eleven patients (female n = 3, male n = 8; age: median 66 years, range 44-81 years) underwent intraluminal HDR brachytherapy for histologically confirmed endobronchial metastases from non-pulmonary primary tumors of various sites like urogenital tract (n = 5), gastrointestinal tract (n = 3), ear/nose/throat (n = 2) and breast (n = 1). The median time between diagnosis of the primary non-bronchogenic tumor and histopathological diagnosis of the endobronchial metastases was 39 months, range 1-99 months. A total dose of 15-20 Gy was delivered in three to four fractions of 5-6 Gy once a week. No palliative chemotherapy was added. RESULTS: Median follow-up after palliative brachytherapy was 15 months (range 1.4-59 months). Objectively, complete endoscopic response was observed in three (27%) patients, and in five (46%) others partial opening of the initially obstructed airway was achieved. Treatment was judged unsuccessful in three (27%) patients. No patient showed up with local progression. At date of analysis five patients were alive with documented residual tumor (80%) or complete response (20%). Relief of symptoms occurred in the vast majority of patients (n = 8, 73%). CONCLUSION: HDR intraluminal brachytherapy palliates symptoms in patients suffering from endobronchial metastases of non-pulmonary primary tumors. The applied treatment is a safe, effective and well tolerated palliative procedure leading to an improved patient quality of life.