Clinical aspects of tumour involvement of the pulmonary vessels.

The involvement of the pulmonary vessels by tumour emboli may lead to a clinical picture defined as 'subacute cor pulmonale'. Information about this syndrome has been limited to case reports and a few series. A study of 214 autopsied cancer patients was undertaken to investigate the clinical signs and symptoms of tumour involvement of the pulmonary vessels (TIPV). The lungs were removed as a block and 15 sections (3 from each lobe) were analyzed. Clinical data about right ventricular failure, dyspnoea, cough, pleuritic chest pain, cyanosis, engorgement of jugular veins, peripheral oedema, haemoptysis and haemoptoic sputum were obtained from the medical records of each patient. Tumour emboli were detected in 89 cases, and no respiratory symptoms were recorded in 39. The presence of dyspnoea and cyanosis were highly significant in the group with TIVP, and right ventricular failure and peripheral oedema showed slight significant differences between the patients with and without TIPV. The classical picture of subacute cor pulmonale was observed in 13 patients and TIPV was considered to be the main cause of death in 29 cases. Our results indicate that although the development of subacute cor pulmonale was rare in patients with cancer, TIPV may be suspected when the patient presents respiratory distress and should be included in the differential diagnosis of dyspnoea in cancer patients.     

Cisapride decreases prolonged episodes of reflux in infants

Twenty-nine infants (2-4 months old), with pathological gastroesophageal reflux assessed by 24-h esophageal pH monitoring, were studied. Cisapride or placebo was randomly added to positional treatment, prone-antiTrendelenburg position, which was applied to all infants. The pH monitoring was repeated after 13-16 days of treatment and revealed a significant improvement in both groups for most parameters. But the number of reflux episodes lasting longer than 5 min and the total number of reflux episodes had not decreased significantly in the placebo group. Only in the number of reflux episodes lasting longer than 5 min was improvement during treatment significantly greater in the cisapride group. This suggests cisapride both prevented reflux and improved esophageal clearance. These results suggest that in addition to other therapeutic measurements, such as positional treatment (which was previously demonstrated to be effective in this age group), cisapride might be of benefit in the treatment of gastroesophageal reflux disease.     

Digitalis poisoning from medicinal herbs. Two different mechanisms of production]

Two cases of digitalis toxicity due to uncontrolled ingestion of medicinal herbs are presented. The first of them was caused by oleander (Nerium oleander); digoxinemia levels were very high in this patient (4.44 ng/l), who presented many brady- and tachyarrhythmias. These arrhythmias disappeared when digoxinemia returned to normal values. The second patient had atrial fibrillation with slow ventricular rate, severe hypokalemia (2.1 mEq/l) and normal digoxinemia levels. He was taking medicinal herbs for a cold, with sorbitol between its components. Sorbitol may be similar to mannitol and glycerol (osmotic diuretic drugs) when taken at high doses. Uncontrolled ingestion of medicinal herbs is not safe, and severe poisoning can occur.     

Molecular genetic studies in alpha-thalassemia]

A group of 5,000 patients, suspected of haemolytic anaemia, were investigated with molecular genetic methods for deletion types of alpha-thalassemia. In 776 (15.6%) patients a deletion of one or more alpha-globin genes was found. The same group of patients was also investigated for abnormal haemoglobins and beta-thalassaemia. In about 30% of the patients either an alpha-thalassaemia, an abnormal haemoglobin, a beta-thalassaemia, or a combination was diagnosed. In a group of patients with a haemoglobinopathy, the frequency of alpha-thalassaemia was much higher (i.e. 33%) than in individuals without haemoglobinopathy. Preselection of the patients based on the presence of microcytic erythrocytes and/or a decreased ADW0.5 of the erythrocytes gave a high incidence of false-negative and false-positive results. Therefore, haemoglobin examination should not be restricted to protein chemistry, but should include molecular genetic investigations for deletion types of alpha-thalassaemia.     

Spatial Learning Deficits in Mice with a Targeted Glucocorticoid Receptor Gene Disruption

Previous studies in rats using the Morris water maze suggested that the processing of spatial information is modulated by corticosteroid hormones through mineralocorticoid and glucocorticoid receptors in the hippocampus. Mineralocorticoid receptors appear to be involved in the modulation of explorative behaviour, while additional activation of glucocorticoid receptors facilitates the storage of information. In the present study we used the water maze task to examine spatial learning and memory in mice homozygous and heterozygous for a targeted disruption of the glucocorticoid receptor gene. Compared with wild-type controls, homozygous and heterozygous mice were impaired in the processing of spatial but not visual information. Homozygous mutants performed variably during training, without specific platform-directed search strategies. The spatial learning disability was partly compensated for by increased motor activity. The deficits were indicative of a dysfunction of glucocorticoid receptors as well as of mineralocorticoid receptors. Although the heterozygous mice performed similarly to wild-type mice with respect to latency to find the platform, their strategy was more similar to that of the homozygous mice. Glucocorticoid receptor-related long-term spatial memory was impaired. The increased behavioural reactivity of the heterozygous mice in the open field points to a more prominent mineralocorticoid receptor-mediated function. The findings indicate that (i) the glucocorticoid receptor is of critical importance for the control of spatial behavioural functions, and (ii) mineralocorticoid receptor-mediated effects on this behaviour require interaction with functional glucocorticoid receptors. Until the development of site-specific, inducible glucocorticoid receptor mutants, glucocorticoid receptor-knockout mice present the only animal model for the study of corticosteroid-mediated effects in the complete absence of a functional receptor.     

Identification of free and conjugated ecdysteroids in cercariae of the schistosome Trichobilharzia ocellata.

Extracts of cercariae of the avian schistosome Trichobilharzia ocellata were analysed for the presence of ecdysteroids by radioimmunoassay, high-performance liquid chromatography monitoring fractions by radioimmunoassay, and gas chromatography/mass spectrometry (selected ion monitoring). Both free ecdysteroids and polar conjugated ecdysteroids were detected in the cercarial extracts. The free ecdysteroid fraction, as well as the hydrolysed polar conjugated ecdysteroid fraction, contained both ecdysone and 20-hydroxyecdysone in approximately equal amounts. The amount of ecdysteroids detected is comparable to those found in other platyhelminths. A possible role for the ecdysteroids in the development of the parasite and/or the interactions between the parasite and its intermediate host, the freshwater snail Lymnaea stagnalis, is discussed.     

Early stress tests following an uncomplicated myocardial infarct: a comparison between symptom-limited and submaximal tests

To compare the diagnostic and prognostic usefulness of symptom-limited versus load-limited submaximal stress testing, 76 patients, during the first week post acute non-complicated myocardial infarction, were submitted to a symptom-limited Naughton-modified protocol stress test. At 2 METs, 3 METs and maximal effort levels, the tests were classified as positive or negative following the currently used criteria. After a mean follow-up of 15 months, the symptom-limited protocol showed the best sensitivity (95%), specificity (78%), positive (64%) and negative (98%) predictive value, and also the highest risk ratio (27.4) for prediction of subsequent coronary events (2p less than 0.01 vs 2 METs, 3 METs and 2D-Echocardiogram results). Forward stepped multiple correlation analysis indicated independent prognostic value for the results of the symptom-limited stress test (R2: .52 p less than 0.01) and for the location of the myocardial infarction (R2: .05 p less than 0.05) only. In addition, the discriminant prognostic power of the symptom-limited protocol was significant after the fourth month of follow-up (2p less than 0.05 vs submaximal tests and 2D-Echo). Therefore, we recommend the performance of a symptom-limited stress test during the first week post acute non-complicated myocardial infarction, provided that all coronary active medication has been withheld 24 hours before the test.     

EEG and evoked potentials in a series of 21 patients with lissencephaly type I.

Twenty-one Dutch patients were the subject of an extensive study into lissencephaly type I. One hundred and fourteen EEG's of these patients were studied. The EEG's were compared to 52 EEG's recorded from 21 patients with an atypical cortical dysplasia and to a control group consisting of 882 EEG's recorded from 823 patients for various reasons. The EEG's in the lissencephaly patients showed the following patterns significantly more often: (a) generalized fast activity (8-18/s) with an amplitude higher than 50 microV, (c) sharp- and slow-wave complexes with an amplitude higher than 500 microV, (d) an alternating pattern consisting of bursts of sharp waves alternating with periods of electrocerebral depression. Ninety-five percent of the lissencephaly patients showed pattern (a) or (c) or both compared to only 5% of the patients with an atypical cortical dysplasia and 0.4% in the controls. The SSEP's recorded in ten patients after stimulation of the median nerve were abnormal in all. EEG and evoked potentials appear to be valuable examinations in the (differential) diagnosis of lissencephaly type I.     

The presence of an HLA-identical sibling donor has no impact on outcome of patients with high-risk MDS or secondary AML (sAML) treated with intensive chemotherapy followed by transplantation: results of a prospective study of the EORTC, EBMT, SAKK and GIMEMA Leukemia Groups (EORTC study 06921).

This report used the framework of a large European study to investigate the outcome of patients with and without an HLA-identical sibling donor on an intention-to-treat basis. After a common remission-induction and consolidation course, patients with an HLA-identical sibling donor were scheduled for allogeneic transplantation and patients lacking a donor for autologous transplantation. In all, 159 patients alive at 8 weeks from the start of treatment were included in the present analysis. In total, 52 patients had a donor, 65 patients did not have a donor and in 42 patients the availability of a donor was not assessed. Out of 52 patients, 36 (69%) with a donor underwent allogeneic transplantation (28 in CR1). Out of 65 patients, 33 (49%) received an autograft (27 in CR1). The actuarial survival rates at 4 years were 33.3% (s.e. = 6.7%) for patients with a donor and 39.0% (s.e. = 6.5%) for patients without a donor (P = 0.18). Event-free survival rates were 23.1% (s.e. = 6.2%) and 21.5% (s.e. = 5.3%), respectively (P = 0.66). Correction for alternative donor transplants did not substantially alter the survival of the group without a donor. Also, the survival in the various cytogenetic risk groups was not significantly different when comparing the donor vs the no-donor group. This analysis shows that patients with high-risk myelodysplastic syndrome and secondary acute myeloid leukemia may benefit from both allogeneic and autologous transplantation. We were unable to demonstrate a survival advantage for patients with a donor compared to patients without a donor.     

Increased cell death after therapy with an Arg-Gly-Asp-linked somatostatin analog.

Receptor-targeted scintigraphy and radionuclide therapy with radiolabeled somatostatin analogs are successfully applied for somatostatin receptor-positive tumors. The synergistic effects of an apoptosis-inducing factor, for example, the Arg-Gly-Asp (RGD) motif, can increase the radiotherapeutic efficacy of these peptides. Hence, the tumoricidal effects of the hybrid peptide RGD-diethylaminetriaminepentaacetic acid (DTPA)-Tyr3-octreotate (cyclic[c](Arg-Gly-Asp-D-Tyr-Asp)-Lys(DTPA)-D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr), hereafter referred to as RGD-DTPA-octreotate, were evaluated in comparison with those of RGD (c(Arg-Gly-Asp-D-Tyr-Asp)) and Tyr3-octreotate (D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr). METHODS: The therapeutic effects of RGD-111In-DTPA-octreotate, 111In-DTPA-RGD, and 111In-DTPA-Tyr3-octreotate were investigated with various cell lines by use of a colony-forming assay, and caspase-3 activity was also determined. RESULTS: Tumoricidal effects were found with 111In-DTPA-RGD, 111In-DTPA-Tyr3-octreotate, and RGD-111In-DTPA-octreotate, in order from least effective to most effective. Also, the largest increase in caspase-3 levels was found with RGD-111In-DTPA-octreotate. CONCLUSION: RGD-111In-DTPA-octreotate has more pronounced tumoricidal effects than 111In-DTPA-RGD and 111In-DTPA-Tyr3-octreotate, because of increased apoptosis, as indicated by increased caspase-3 activity.