In vivo evaluation of the acute thrombogenicity of the modified human umbilical vein and autologous artery

With the aim to evaluate acute thrombogenicity, segments of human umbilical vein grafts (Dardik Biograft, Meadox Medicals, Inc., Oakland, N.J.), nonheparinized, heparin-alcohol-treated, or covalently heparinized, were implanted into the carotid arteries of sheep. Autologous carotid arteries were used as control grafts. Flow was restricted to 25 ml/min. Accumulation of autologous 32P-labeled platelets was registered at both anastomotic and midgraft regions for 240 minutes. At the end of the perfusion period, grafts were removed, opened longitudinally, and the thrombus-free surface (TFS) and thrombus weight determined. The ex vivo determinations showed good correlation with results obtained with in vivo registration. In vivo accumulation of platelets was significantly larger in nonheparinized human umbilical vein grafts compared with heparin-alcohol treated grafts. Covalently heparinized grafts showed a tendency toward lower radioactive values, but visual examination after perfusion revealed areas of "intimal" damage with thrombotic deposits, probably caused by heparinization procedure. Autologous arteries showed the largest TFS and the smallest thrombi. Platelet accumulation in autologous arteries decreased almost to reference values after an initial rapid increase. In conclusion, heparin-alcohol treatment of human umbilical vein grafts reduces acute thrombogenicity. Although covalent heparin bonding seems to act in the same way, the fragility of the graft appears to preclude use of this method. Autologous arteries exhibit excellent antithrombotic characteristics.     

Defective glucose-stimulated insulin release in the diabetic Goto-Kakizaki (GK) rat coincides with reduced activity of the islet carbon monoxide signaling pathway

The Goto-Kakizaki (GK) rat displays a markedly reduced insulin response to glucose, a defect that is thought to be coupled to an impaired glucose signaling in the beta-cell. We have examined whether carbon monoxide (CO), derived from beta-cell heme oxygenase (HO), might be involved in the secretory dysfunction. Immunocytochemical labeling of constitutive HO (HO-2) showed no overt difference in fluorescence pattern in islets from GK vs. Wistar controls. However, isolated islets from GK rats displayed a markedly impaired HO activity measured as CO production (-50%), and immunoblotting revealed an approximately 50% reduction of HO-2 protein expression compared with Wistar controls. Furthermore, there was a prominent expression of inducible HO (HO-1) in GK islets. Incubation of isolated islets showed that the glucose-stimulated CO production and the glucose-stimulated insulin response were considerably reduced in GK islets compared with Wistar islets. Addition of the HO activator hemin or gaseous CO to the incubation media brought about a similar amplification of glucose-stimulated insulin release in GK and Wistar islets, suggesting that distal steps in the HO-CO signaling pathway were not appreciably affected. We conclude that the defective insulin response to glucose in the GK rat can be explained, at least in part, by a marked impairment of the glucose-HO-CO signaling pathway as manifested by a prominent decrease in glucose stimulation of islet CO production and a reduced expression of HO-2. A possible role of HO-1 expression as a compensatory mechanism in the GK islets is presently unclear.     

Agonist-specific patterns of β2-adrenoceptor responses in human airway cells during prolonged exposure

Background and purpose:

β₂-Adrenoceptor agonists (β₂-agonists) are important bronchodilators used in the treatment of asthma and chronic obstructive pulmonary disease. At the molecular level, β₂-adrenergic agonist stimulation induces desensitization of the β₂-adrenoceptor. In this study, we have examined the relationships between initial effect and subsequent reduction of responsiveness to restimulation for a panel of β₂-agonists in cellular and in vitro tissue models.

Experimental approach:

β₂-Adrenoceptor-induced responses and subsequent loss of receptor responsiveness were studied in primary human airway smooth muscle cells and bronchial epithelial cells by measuring cAMP production. Receptor responsiveness was compared at equi-effective concentrations, either after continuous incubation for 24 h or after a 1 h pulse exposure followed by a 23 h washout. Key findings were confirmed in guinea pig tracheal preparations in vitro.

Key results:

There were differences in the reduction of receptor responsiveness in human airway cells and in vitro guinea pig trachea by a panel of β₂-agonists. When restimulation occurred immediately after continuous incubation, loss of responsiveness correlated with initial effect for all agonists. After the 1 h pulse exposure, differences between agonists emerged, for example isoprenaline and formoterol induced the least reduction of responsiveness. High lipophilicity was, to some extent, predictive of loss of responsiveness, but other factors appeared to be involved in determining the relationships between effect and subsequent loss of responsiveness for individual agonists.

Conclusions and implications:

There were clear differences in the ability of different β₂ agonists to induce loss of receptor responsiveness at equi-effective concentrations.     

Specific nasal symptoms and symptom-provoking factors may predict increased risk of developing COPD

In a 1992 questionnaire study, we found that certain nasal symptoms and symptom-provoking factors were associated with prevalence of self-reported chronic bronchitis/emphysema (CBE). In this follow-up study, we examined whether any nasal features could predict an increased incidence of self-reported physician's diagnosis of CBE/chronic obstructive pulmonary disease (COPD). In 2000, a survey was performed similar to the one in 1992. Of a paired follow-up group of 4933 participants aged 28-67 years, 4280 (86.8%) returned the questionnaire. Odds ratios (ORs) for cumulative incidence (between 1992 and 2000) of self-reported physician-diagnosed CBE/COPD and asthma, respectively, were calculated by logistic regression with adjustment for age, gender and smoking habits. Reports of thick, yellow nasal discharge and nasal blockage in 1992 predicted incidence of CBE/COPD: OR 2.3 (1.2-4.2) and 1.8 (1.1-2.8) respectively. Moreover, nasal symptoms provoked by exposure to damp/cold air and tobacco smoke predicted CBE/COPD: OR 3.4 (1.9-6.0) and 2.5 (1.4-4.2). Nasal itching and nasal symptoms provoked by exposure to grass pollen and furred animals predicted incidence of asthma. These results suggest that certain nasal symptoms and nasal symptom-provoking exposures, different from those commonly associated with asthma, may predict increased risk of developing CBE/COPD. This supports the possibility of nasal co-morbidity in COPD.     

Irradiation of myxoid/round cell liposarcoma induces volume reduction and lipoma-like morphology

The aim of the study was to investigate the clinical and morphological effects of radiotherapy in the treatment of myxoid/round cell liposarcoma (MLS/RCLS). Thirty-three primary and metastatic MLS/RCLS tumours in 15 patients were treated with radiation therapy. Twenty-seven of the 33 tumours were surgically removed after preoperative radiation (34-46 Gy) while six tumours were treated with radiotherapy alone (44-60 Gy). The pretreatment diagnosis was established in all 15 patients based on fine needle aspirates or histological findings. Tumour size was measured by CT or MRI before and after radiotherapy in 30 tumours. Thirteen tumours from 11 patients were genetically characterised before and/or after radiation therapy. Twenty-three of 30 irradiated tumours showed a median reduction in tumour volume of 52% and seven lesions a median progression of 36%. All 27 surgically removed tumours revealed histological features of radiation response. The most striking morphological changes were lipoma-like appearance, paucicellularity and hyalinisation. Twelve of 13 tumours analysed before and/or after radiation therapy showed the FUS-DDIT3 translocation. Radiation therapy of MLS/RCLS induces histopathologic accumulation of mature lipoma-like areas and tumour volume reduction that may facilitate resectability.