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Biomedical subjects

A Schweizer

Publications and source records attributed to A Schweizer.

At least 37 records · Page 2Linked to original sources
PubMed1999

Neonatal lethality in mice deficient in XCE, a novel member of the endothelin-converting enzyme and neutral endopeptidase family.

XCE, a new member of the endothelin-converting enzyme and neutral endopeptidase family, is preferentially expressed in specific areas of the central nervous system including spinal chord and medulla. To elucidate the importance and function of XCE, we disrupted its gene in mouse embryonic stem cells by homologous recombination and created mice deficient in XCE. The resulting phenotype is characterized by neonatal lethality. All XCE -/- homozygous mice died of respiratory failure shortly after birth, and in most cases their lungs were never ventilated. Apart from the atelectasis, anatomical and histological examinations of embryonic day 18.5 XCE -/- embryos and newborn homozygotes did not reveal any obvious abnormalities in organs and tissues. Malformations that are related to the knock-out were also not found in the skeletons of XCE -/- mice. In addition, XCE knock-out animals showed no deficiency of pulmonary surfactant proteins and had normal heart beat frequencies. Taken together, our results demonstrate that XCE is an essential gene. The phenotype of the XCE-deficient mice together with the central nervous system-specific expression further suggest that XCE may play a vital role in the control of respiration.

Animals↗
PubMed1999

Palmitoylation of the three isoforms of human endothelin-converting enzyme-1.

Endothelin-converting enzyme-1 (ECE-1) is a membrane-bound metalloprotease that catalyses the conversion of inactive big endothelins into active endothelins. Here we have examined whether the three isoforms of human ECE-1 (ECE-1a, ECE-1b and ECE-1c) are modified by the covalent attachment of the fatty acid palmitate and have evaluated a potential functional role of this modification. To do this, wild-type and mutant enzymes were expressed and analysed by metabolic labelling with [3H]palmitate, immunoprecipitation and SDS/PAGE. All three ECE-1 isoforms were found to be palmitoylated via hydroxylamine-sensitive thioester bonds. In addition, the isoforms showed similar levels of acylation. Cys46 in ECE-1a, Cys58 in ECE-1b and Cys42 in ECE-1c were identified as sites of palmitoylation and each of these cysteines accounted for all the palmitoylation that occured in the corresponding isoform. Immunofluorescence analysis demonstrated further that palmitoylated and non-palmitoylated ECE-1 isoforms had the same subcellular localizations. Moreover, complete solubility of the three isoforms in Triton X-100 revealed that palmitoylation does not target ECE-1 to cholesterol and sphingolipid-rich membrane domains or caveolae. The enzymic activities of ECE-1a, ECE-1b and ECE-1c were also not significantly affected by the absence of palmitoylation.

Acylation↗
PubMed1999

XCE, a new member of the endothelin-converting enzyme and neutral endopeptidase family, is preferentially expressed in the CNS.

In the present study, we have isolated a cDNA encoding a novel member of the family of zinc metallopeptidases that includes neutral endopeptidase and endothelin-converting enzyme. The predicted amino-acid sequence of this enzyme, termed XCE, consists of 775 amino-acids with a single putative membrane-spanning region, an N-terminal cytoplasmic domain of 59 residues, and a large luminal domain that contains a characteristic zinc-binding motif. Western blot analysis of cells stably expressing this new metallopeptidase revealed a glycosylated protein of approximately 95 kDa. XCE mRNA was found to be predominantly expressed in the central nervous system, sympathetic ganglia and in uterine subepithelial cells. In the rat and human CNS, a very specific pattern of neuronal labelling (in presumptive cholinergic interneurons of basal ganglia, basal forebrain neurons, as well as brainstem and spinal cord motoneurons) was detected by in situ hybridization histochemistry. The enzyme substrate, as yet unidentified, might be found among the numerous neuropeptide transmitters which are colocalized with acetylcholine in these neurons.

Amino Acid Sequence↗
PubMed1999

Chronic angiotensin converting inhibition does not influence renal hemodynamic and function during cardiac surgery.

PURPOSE: Treatment with angiotensin-converting enzyme (ACE) inhibitors affects the autoregulation of renal blood flow and glomerular filtration and provides renal protective effects. The purpose of this case-control study was to investigate the effects of chronic ACE inhibition on perioperative renal hemodynamics and function. METHOD: We prospectively studied renal function in two groups of patients, chronically treated or not, with ACE inhibitors (ACEI and control; n = 16, in each group) who underwent elective cardiac surgery under hypothermic cardiopulmonary bypass. Glomerular filtration rate, effective renal plasma flow, osmolar clearance and fractional excretion of sodium and potassium were determined before, during and after CPB. Additional measurements included plasma atrial natriuretic factor (ANF) as well as plasma and urinary cyclic GMP (cGMP), thromboxane B2 (TxB2) and 6-keto-PGF1. RESULTS: Renal functional and hemodynamic variables did not differ between the two groups, at any period. Cardiopulmonary bypass induced increases in urinary flow, osmolar clearance and fractional excretion of sodium and potassium in both groups. Plasma and urinary ratio of 6-keto-PGF to TxB2 increased markedly and reflected a predominant systemic and renal release of vasodilatory prostaglandins. Intraoperatively, ANF was higher in ACEIs than in control patients. CONCLUSIONS: Long term treatment with ACE inhibitors does not influence the perioperative changes in renal hemodynamics and function. During cardiopulmonary bypass, a transient impairment in solute reabsorption is associated with renal release of vasodilatory mediators (nitric oxide and prostacyclin).

Aged↗
PubMed1999

Partial left ventriculectomy combined with transmyocardial laser revascularization.

We report the use of transmyocardial laser revascularization in combination with partial left ventriculectomy for treatment of end-stage dilated ischemic cardiomyopathy. The disappearance of the reversible perfusion defects in the treated left ventricular territories and improvement of the systolic function led us to believe that the simultaneous use of these two techniques was complementary in our patient.

Adult↗
PubMed1999

Percutaneous tenodesis of the Achilles tendon. A new surgical method for the treatment of acute Achilles tendon rupture through percutaneous tenodesis.

Various studies have shown that the operative treatment of a freshly ruptured Achilles tendon is generally considered to be more appropriate than a nonoperative regimen. However, complications in open reconstructions are reported to occur between 11-29%. We intended to develop a method which reduces the risk of complications arising from operation but simultaneously allows early postoperative mobilization and functional treatment. We developed a percutaneous tenodesis of the Achilles tendon, using two Lengemann extension wires for adaptation of the ruptured tendon. This method of treatment has been applied in 20 patients. The postoperative observation period was one year. All patients were male, their average age was 42 years. The Achilles tendon ruptures occurred during sporting activities and were treated by operation within 22 h on average. The outcome was very good in 95%. One patient (5%) suffered a rerupture due to trauma. There was no other complication.

Achilles Tendon↗
PubMed1999

Perioperative mortality and major cardio-pulmonary complications after lung surgery for non-small cell carcinoma.

OBJECTIVES: A database of patients operated of lung cancer was analyzed to evaluate the predictive risk factors of operative deaths and life-threatening cardiopulmonary complications. METHODS: From 1990 to 1997, data were collected concerning 634 consecutive patients undergoing lung resection for non-small cell carcinoma in an academic medical centre and a regional hospital. Operations were managed by a team of experienced surgeons, anaesthesiologists and chest physicians. Operative mortality was defined as death within 30 days of operation and/or intra-hospital death. Respiratory failure, myocardial infarct, heart failure, pulmonary embolism and stroke were considered as major non-fatal complications. Preoperative risk factors, extent of surgery, pTNM staging, perioperative mortality and major cardiopulmonary complications were recorded and evaluated using chi-square statistics and multivariate logistic regression. RESULTS: Complete data were obtained in 621 cases. The overall operative mortality was 3.2% (n = 19). Cardiovascular complications (n = 10), haemorrhage (n = 4) and sepsis or acute lung injury (n = 5) were incriminated as the main causative factors. In addition, there were 13 life-threatening complications (2.1%) consisting in strokes (n = 4), myocardial infarcts (n = 5), pulmonary embolisms (n = 1), acute lung injury (n = 1) and respiratory failure (n = 2). Four independent predictors of operative death were identified: pneumonectomy, evidence of coronary artery disease (CAD), ASA class 3 or 4 and period 1990-93. In addition, the risk of major complications was increased in hypertensive patients and in those belonging to ASA class 3 or 4. A trend towards improved outcome was observed during the second period, from 1994 to 97. CONCLUSION: Our data demonstrate that perioperative mortality is mainly dependent on the extent of surgery, the presence of CAD and provision of adequate medical and nursing care. Preoperative testing and interventions to reduce the cardiovascular risk factors may help to further improve perioperative outcome.

Adenocarcinoma↗
PubMed1999

Beneficial effects of leukocyte-depleted blood and low-potassium dextran solutions on microvascular permeability in preserved porcine lung.

Modified Euro-Collins (EC) solution, a crystalloid intracellular-type solution, has been commonly used for pulmonary preservation. Several experimental studies have shown the advantages of using extracellular colloid-based solutions. The aim of this study was to compare the quality of preservation of two extracellular colloid solutions, leukocyte-depleted blood (BL) and low-potassium dextran (LPD) solutions, with that of EC solution. Lungs of 22 domestic pigs were flushed and preserved with EC (n = 8), BL (n = 7), or LPD (n = 7) solution. After harvesting, one of the lungs was reperfused immediately in an ex vivo circuit (control lungs), whereas the contralateral lung was reperfused after 8 h of cold (4 degrees C) storage (preserved lungs). Besides the lung function parameters (gas exchange, pulmonary hemodynamics and mechanics), the permeability of the endothelial-epithelial barrier was assessed by determining the transferrin leak index (TLI) using a double radioisotopic method, by measuring the alveolar/arterial protein concentration ratio, and by analyzing histopathologic changes. The functional quality (oxygenation, airway resistance, dynamic compliance [CL, dyn]) of both BL and LPD lungs was slightly but significantly superior to that of EC lungs. However, pulmonary vascular resistance was lower in BL-preserved than in EC- or LPD-preserved lungs. The TLI was increased in EC control and preserved lungs, whereas it was low in BL and LPD control lungs and did not increase after preservation. The alveolar/arterial protein concentration ratio was not different between control groups, but was increased fourfold in EC-preserved compared with BL- or LPD-preserved lungs. Finally, EC-preserved lungs presented a weight gain about twice that of BL- and LPD-preserved lungs. Morphologic analysis confirmed these results, because in the EC-preserved lungs, rupture of alveolar septa and severe alveolar edema and hemorrhage were observed, whereas BL- and LPD-preserved lungs showed a relatively well-preserved structure. The results demonstrate that both BL and LPD flush solutions preserve the endothelial-epithelial barrier better than does EC solution. Although the quality of preservation is similar, pulmonary vascular resistance is higher in LPD-preserved than in BL-preserved lungs.

Animals↗
PubMed1999

Two di-leucine-based motifs account for the different subcellular localizations of the human endothelin-converting enzyme (ECE-1) isoforms.

Endothelin-converting enzyme (ECE-1) is a type II integral membrane protein which plays a key role in the biosynthetic pathway of the vasoconstricting endothelins. Three ECE-1 isoforms, differing by their N-terminal cytoplasmic tails, are generated from a single gene. When expressed in CHO cells, they display comparable enzymatic activity but whereas ECE-1a is strongly expressed at the cell surface, ECE-1b is exclusively intracellular and ECE-1c presents an intermediate distribution. In the present study these different localizations were further described at the ultrastructural level, by electron microscope immunocytochemistry. To characterize the motifs responsible for the intracellular localization of ECE-1b we constructed chimeric proteins and point mutants. Two di-leucine-based motifs, contained in the N-terminal part of ECE-1b, were thus identified. One of these motifs (LV), displayed by both ECE-1b and ECE-1c, accounts for the reduced surface expression of ECE-1c as compared to ECE-1a. Mutation of both motifs (LL and LV) induces a very strong appearance of ECE-1b at the cell surface indicating that their presence in the N-terminal extremity of ECE-1b is critical for its exclusively intracellular localization.

Amino Acid Motifs↗
PubMed1998

[Surgical treatment of severe emphysema: lung transplantation or volume reduction?].

In recent years, lung transplantation (LT) and volume reduction surgery (LVRS) have been proposed for selected patients with end-stage pulmonary emphysema. Retrospectively, we analyzed the perioperative time course of 30 patients with emphysema who underwent either LVRS (n = 17) or LT (n = 13). In the LVRS group, patients were significantly older, presented less severe functional disability and all but one could be extubated at the end of surgery. In contrast, patients undergoing LT required postoperative mechanical ventilation (19 +/- 11 hrs) and had a prolonged hospital stay (37 [25-60] days vs 19 [11-42] days in LVRS patients) due to reperfusion lung edema, infection, hemorrhage and acute rejection. Six months postoperatively, forced expiratory volume in 1 second was improved and was significantly larger after LT compared with LVRS (+200% vs +63%). Our preliminary results suggest that, although LT produces greater functional improvement, LVRS is associated with lower surgical risk and is an alternative therapy in selected patients with severe emphysema.

Aged↗
PubMed1998

A new family of orphan G protein-coupled receptors predominantly expressed in the brain.

The cloning of a cDNA encoding a G protein-coupled receptor homologous to the endothelin type B receptor, but unable to bind endothelin, was recently reported and termed ET(B)R-LP. We report here the isolation of a human cDNA encoding a receptor that is highly related to ET(B)R-LP and which was therefore termed ET(B)R-LP-2. Comparison of the two amino acid sequences revealed 68% overall homology and 48% identity. As is the case for ET(B)R-LP, the new receptor is strongly expressed in the human central nervous system (e.g. in cerebellar Bergmann glia, cerebral cortex, internal capsule fibers). Membranes of HEK-293 cells stably expressing ET(B)R-LP-2 did not bind endothelin-1, endothelin-2, endothelin-3, bombesin, cholecystokinin-8 or gastrin-releasing peptide.

Amino Acid Sequence↗
PubMed1998

Massive contralateral pneumonia following thoracotomy for lung resection.

Separation of the lungs with a double-lumen endobronchial tube facilitates the surgical approach and protects the bronchial system from contamination by pus or blood from the operated lung. We report a case of a 49-year-old man who suffered a gram-negative pneumonia requiring mechanical ventilatory support and prolonged hospitalization after pulmonary resection. Contamination of the ventilated-dependent lung was documented intraoperatively. Current information on postoperative infectious complications and preventive measures are discussed.

Airway Obstruction↗
PubMed1998

Benefits of intraoperative skin surface warming in cardiac surgical patients.

We have investigated patients undergoing cardiac surgery with hypothermic bypass to see if the addition of skin surface warming during systemic rewarming on bypass (heated group, n = 43) would improve perioperative thermal balance compared with conventional management without skin warming (control group, n = 43) in an open, randomized, controlled study. Intraoperative skin warming with a water mattress and forced warm air over the face, neck and shoulders attenuated the afterdrop in nasopharyngeal temperature after weaning from bypass (2.3 (1.2) degrees C and 1.3 (0.5) degrees C in the control and heated groups, respectively) (P < 0.05) and resulted in higher rectal temperature 4 h after surgery. Despite similar standard coagulation tests, heated patients had lower blood loss via the chest tubes (600 (264) ml vs 956 (448) ml in control patients) (P < 0.05) and less requirements for i.v. colloid infusion (1662 (404) ml vs 1994 (389) ml) (P < 0.05). There was a significant inverse correlation between rectal temperature on arrival in the ICU and postoperative blood loss (r = 0.57, P < 0.001). These data suggest that additional skin surface warming with a water mattress and forced warm air helped to preserve perioperative thermal balance and may contribute to reduced bleeding after cardiac surgery.

Adult↗