Dual targeting improves capture of ultrasound microbubbles towards activated platelets but yields no additional benefit for imaging of arterial thrombosis.

Platelets can be found on the surface of inflamed and ruptured atherosclerotic plaques. Thus, targeting of activated platelets may allow for molecular imaging of vulnerable atherosclerotic lesions. We here investigated microbubbles (MB) functionalized with the selectin ligand sialyl Lewisa individually (MBsLea) or dually with sLea and an antibody targeting ligand-induced binding sites of the activated GPIIb/IIIa receptor (MBDual). Assessed by in vitro flow chamber, targeted MB exhibited increased adhesion to platelets as compared to MBControl. While MBsLea rolled slowly on the platelets' surface, MBDual enhanced the percentage of firm adhesion. In vivo, MB were investigated by ultrasound in a model of ferric chloride induced non-occlusive carotid artery thrombosis. MBsLea and MBDual revealed a higher ultrasound mean acoustic intensity than MBControl (p < 0.05), however MBDual demonstrated no additional increase in mean signal intensity as compared to MBsLea. The degree of carotid artery stenosis on histology correlated well with the ultrasound acoustic intensity of targeted MB (p < 0.05). While dual targeting of MB using fast binding carbohydrate polymers and specific antibodies is a promising strategy to support adhesion to activated platelets under arterial shear stress, these advantages seem not readily translatable to in vivo models.

Intra-operative assessment of pulmonary artery pressure by transoesophageal echocardiography.

The clinical value of the estimation of systolic pulmonary artery pressure, based on Doppler assessment of peak tricuspid regurgitant velocity using transoesophageal echocardiography, is unclear. We studied 109 patients to evaluate the feasibility of obtaining adequate Doppler recordings, and compared Doppler estimates with values measured using a pulmonary artery catheter in a subset of 33 patients. Tricuspid regurgitation was evaluated at the mid-oesophageal level at 0-120° using Doppler echocardiography. A Doppler signal was defined as adequate if there was a ≤ 20° alignment and a full envelope. Doppler estimates of systolic pulmonary artery pressure within 10 mmHg and 15% of the value recorded with the pulmonary artery catheter were considered to be in sufficient agreement. Adequate Doppler signals were obtained in 64/109 (59%) patients before and 54/103 (52%) after surgery. Doppler estimates by transoesophageal echocardiography were within 10 mmHg and 15% of values recorded with the pulmonary artery catheter in 28/33 (75%) patients and 22/31 (55%) patients, respectively. In 7 (21%) patients, the echocardiographic Doppler measurement exceeded the measured systolic pulmonary artery pressure by more than 30%. Our study indicates that estimation of the systolic pulmonary artery pressure using transoesophageal Doppler echocardiography is not a reliable and clinically useful method in anaesthetised patients undergoing mechanical ventilation.

ErbB-4 mRNA expression is decreased in non-metastatic pancreatic cancer.

The erbB-4 gene encodes a detected receptor protein that possesses intrinsic tyrosine kinase activity and belongs to the family of the epidermal growth factor receptor (EGFR); erbB-4 is stimulated by the heregulins and betacellulin, which enables this receptor to form heterodimers with erbB-2, a prerequisite for erbB-2 activation. Because the expression of erbB-4 mRNA is generally low in the pancreas, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine the erbB-4 levels in human normal and cancerous pancreatic tissue. Our results show that the mRNA expression of this receptor is 6-fold decreased in the non-metastatic stages of pancreatic cancer when compared to tumors with lymph node or distant metastases or to the normal pancreas. In addition, immunohistochemistry demonstrated that in the normal pancreas, the erbB-4 antigen was predominantly present in the cell membrane and cytoplasm of the ductal and acinar cells and at a much lower level, in islet cells. In pancreatic cancer, 61 of 75 samples exhibited weak to moderate immunoreactivity for erbB-4 in the tumor cells. Moreover, in the peri-tumorous region with chronic pancreatitis-like morphological changes, there was weak-to-moderate erbB-4 immunostaining in small ductules and degenerating acinar cells. Uni- and multivariate survival analyses using as variables age, sex, stage of cancer, histo-pathological grading, and erbB-4 immunoreactivity, revealed a significant effect for stage of cancer (p < 0.01) whereby the risk of dying was 2.3 times higher in patients with metastases than in patients without. However, the level of erbB-4 immunoreactivity in pancreatic cancer cells had no influence on patient survival.

Receptor kinetics and concentration-effect relation of cardiac glycosides.

Therapeutic and toxic actions of cardiac glycosides are attributed to an inhibition of Na, K-ATPase. The therapeutically relevant range is between 25% and 50% inhibition. There is a good correlation between the average steady state serum concentration of glycosides and their therapeutic action. However, therapeutic and toxic effects set in with a latency and therefore do not follow the daily variations in glycoside concentration. Although the effect follows the average serum concentrations, only the minimal concentration is measured. In principle this is only adequate if the ratio of average/minimal concentration is constant. A model calculation showed that with a constant average steady state concentration an increase in the distribution volume or a decrease in total body clearance with corresponding reduction of the daily dose lead to an increase of the minimal concentrations of 5-7%. This means a corresponding underestimation of the average concentration from the minimum concentration. However, the deviations are too small to be of clinical relevance.

Inhibition of chemiluminescence in granulocytes and alveolar macrophages by azelastine.

The effect of azelastine, an orally effective antiasthmatic antiallergic drug on the generation of oxygen-derived free radicals in phagocytes was investigated using different chemiluminescence-assays. The chemiluminescence (CL) of both human polymorphonuclear granulocytes (PMNL) and guinea-pig alveolar macrophages (AM) was induced either by phorbol myristate acetate (PMA) or zymosan and amplified either by lucigenin or DMNH (7-dimethylamino-naphthalene-1,2-dicarbonic-acidhydrazide). The inhibitory effect of azelastine was dependent on the inducer employed and the condition and type of cells used. Azelastine reduced PMA-induced CL concentration-dependently in both PMNL (IC30 = 3.9 microM) and AM (IC30 = 9.8 microM). In AM zymosan-induced CL was inhibited 21.7% by 10 microM azelastine, whereas in PMNL it remained unchanged up to 10 microM azelastine. Azelastine has a significantly stronger inhibitory effect (IC30 = 4.2 microM) on oxygen free radical generation in AM primed by fetal calf serum than in unprimed AM. Based on present results it is likely that azelastine inhibits oxygen-derived free radical generation by interaction with protein kinase C.

[Follow-up of children screened at 4 years of age through school age with particular attention the evaluation of speech function]. / Opfølgning i skolealderen af screening af 4-årige børn. Specielt med henblik på vurdering af sprogfunktionen.

The object of this follow-up investigation was to assess the effect of screening investigation of children at the age of four years, with particular attention to hearing, speech and language functions. This screening was carried out by specially trained health visitors and 119 children (61 boys and 58 girls) participated. This corresponded to 87.5% of the selected population. In the cases in which they could be traced, the parents of these children received a questionnaire approximately six years later. Questions were asked about the work of the health visitors at the four-year screening and the present school situation of the child. 65% of the parents replied to this questionnaire. Three questionnaires were sent to the children's schools (when these were known): one to the school health nurse with questions about the results of testing of sight and hearing and whether the child had presented problems or signs of illness, another to the Danish teacher about the child's speech development and fine motor function and whether remedial teaching had proved necessary and a third questionnaire to the gymnastic teacher about motor development and coordination. Information was obtained from the schools about 81% of children. In addition, information was collected from the school psychological office and the speech institute in all of the cases where the children had been involved with these institutions. The material obtained was found to be reasonably representative as regards problems of hearing, speech and language. At the age of four years, a definite connection was found between poor motor function and poor speech function and boys tended to show poorer speech function than girls.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of 14C-activity after the administration of 14C-azimexone in rats.

The pharmacokinetics of 14C-activity were studied in male Sprague-Dawley rats over 24 and 288 h periods after oral i.v. administration respectively. After oral administration rapid and complete absorption of azimexone occurred. The elimination of radioactivity from plasma after i.v. administration could be best described by an open four-compartment-system yielding a terminal half-life of 74.45 h indicating the existence of deep compartment for azimexone or its metabolites. The renal clearance of 14C-activity decreased considerably after i.v. administration with progressing time. This points to an extensive metabolism of azimexone. Fifty-seven and sixty-seven per cent of the given 14C-activity could be recovered in urine within 24 h after i.v. and p.o. administration respectively and in both cases less than 1% of the doses in feces. Studies on the distribution of the labelled substance 24 h after i.v. administration showed highest concentration in gastric contents, spleen thyroid gland and bone marrow. Twelve days after i.v. administration the ratio of the 14C-content in organ/plasma was greatly increased for spleen, thymus, lung, bone marrow and thyroid gland as compared with the conditions 24 h after administration. Thus it can be assumed that the target organs for the immunomodulating activity of the drug belong to the deep compartment of azimexone or its metabolites.