Captopril inhibits in vitro and in vivo the proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation

Angiotensin I-converting enzyme (ACE) has been shown to be involved in the catabolism of the tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP). As AcSDKP is a physiological inhibitor of haematopoietic stem cell proliferation, we investigated the in vitro and in vivo effects of captopril, one of the specific inhibitors of ACE, on the proliferation of primitive haematopoietic cells. Regenerating bone marrow cells obtained from mice given one injection of cytosine arabinoside (100 mg/kg) as well as SA2 myeloid leukaemia cells were incubated in vitro for 24 h with 10-6 M captopril. Captopril significantly reduced the proportion of high proliferative potential colony-forming cells (HPP-CFC-1) in S-phase, whereas it had no effect on the proportion of SA2 leukaemic colony-forming cells in S-phase. When given in vivo to mice 1 h after 2 Gy gamma-irradiation or cytosine arabinoside (AraC) injection, captopril (100 mg/kg) was shown to prevent HPP-CFC-1 entry into S-phase induced by these cytotoxic treatments. The observed effects correlated with a reduction in ACE degradative activity and an increase in the level of endogenous AcSDKP both in the supernatants of captopril-treated bone marrow cells and in plasma of treated animals. The present findings suggest that AcSDKP might mediate the observed in vitro and in vivo inhibitory effects of captopril on primitive haematopoietic cell proliferation.     

Sensitive determination of vinorelbine and its metabolites in human serum using liquid chromatography-electrospray mass spectrometry

A liquid chromatography-electrospray mass spectrometry method was developed for the quantitation of vinorelbine (VNB) and two metabolites, vinorelbine N-oxide (VNO) and deacetyl vinorelbine (DAV) in human serum. The limits of quantitation (LOQ) reached 0.5 ng/ml for both VNB and VNO and 1 ng/ml for DAV. The method was proved linear in the range of LOQs up to 1000 ng/ml, and extraction recovery was 80% on average for the three compounds. It was applied to the pharmacokinetic monitoring of vinorelbine and, for the first time, to the detection of VNO in the serum of patients suffering from non-small-cell lung cancer.     

Left auricular dilatation in calcified aortic stenosis in adults

Two groups of patients of comparable age, one comprising 12 subjects without detectable cardiac disease and the other comprising 38 patients with calcific aortic stenosis (CAS) underwent clinical, electrocardiographic, echocardiographic and haemodynamic studies to assess the degree and significance of left atrial hypertrophies in CAS. The volume of the left atrium (LA) was globally increased in CAS (maximum volume 68 per cent: 26/38) and LA ejection fraction was decreased in 60 per cent of patients (23/38). However, the maximum volume was only moderately greater than that of normal subjects (+38 per cent). The most specific non-invasive investigation for left atrial assessment is echocardiography. There was a linear relationship between LA angiographic volume and echocardiographic antero-posterior dimension (r = 0.43; p less than 1 x 10(-2)). The duration of the P wave in S2 was a specific (75 per cent) but relatively insensitive (27 per cent) sign of LA dilatation in pure CAS. On the other hand, the Morris index based on the surface of the P terminal force in V1 was quite sensitive (77 per cent) but not very specific (25 per cent). The maximum LA volume was not related to left ventricular volume, the severity of CAS, diastolic indices of compliance or left ventricular mass. However, the minimum LA volume (after atrial systole) was related to left ventricular end diastolic (r = 0.35, p less than 0.05) and end systolic volume (r = 0.34, p less than 0.05). The LA ejection fraction was inversely related to mean pulmonary capillary pressure (r = 0.34, p less than 5 x 10(-2).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute myeloid leukemias, multiple myelomas, and chronic leukemias in the setting of HIV infection

B-cell lineage-derived high-grade malignant lymphomas are a well-recognized complication of HIV infection. However, isolated cases of unusual hematologic malignancies such as acute myeloid leukemias (AML), multiple myeloma (MM) or plasmacytomas, and chronic leukemias have been reported. This review focuses on these uncommon malignancies supervening in the setting of HIV infection. Eighteen cases of AML have been reported. Extramedullary localizations are frequently noticed. Nontreated patients have a survival of 2.7 weeks, compared with 9.8 months for patients treated with chemotherapy; being HIV-positive is not a contraindication to the treatment of AML. Based on the observed 72% incidence of AML M4 and M5 in an HIV-infected population versus 19% to 36% expected in a non-HIV-infected population, we postulate that the association of AML and HIV is not coincidental. The monocytotropism of HIV, the chronic cytokine-mediated activation of monocytes/macrophages, and the immunodeficiency may explain this association. Twenty-two cases of MM or plasmacytomas have been described, most of them in young patients. Again, extramedullary plasma cell tumors are recorded in many patients. Physiopathologic studies suggest that MM may develop because of an antigen-driven response to the circulating viral antigens. A role for Epstein-Barr virus (EBV) in the pathogenesis, as previously described in high-grade non-Hodgkin's lymphomas, is suggested by the presence of EBV genomes in plasma cell tumors. Finally, a broad spectrum of chronic leukemias derived from B- or T-cell lymphocyte lineage has been reported. These associations seem coincidental.     

Significance of hemiblock of the left branch during exercise

There have been few reports of exercise induced left branch hemiblock. In order to assess its frequency and significance, a retrospective study of 8684 patients was undertaken: 24 cases (11 anterior and 13 posterior) were recensed. Nineteen of these patients had typical effort angina, 3 had a history of myocardial infarction and 3 had aortiocoronary bypass surgery. Twenty patients developed ST-T wave abnormalities included 11 ST segment depressions. Four patients refused coronary angiography: 3 of these patients had probable coronary artery disease (typical effort angina, positive exercise stress tests and in 1 case, inferior wall hypofixation during myocardial scintigraphy). Twenty patients underwent coronary angiography. In 2 patients, the exercise stress test was performed under Class IC antiarrhythmic therapy; 1 had a normal coronary angiogram and the other had patient coronary bypass graft. A control exercise stress test after withdrawal of drug therapy was negative in these 2 cases. The other 18 patients had significant coronary artery disease. The recording of left branch hemiblock during exercise stress testing would seem to indicate severe coronary artery narrowing (greater than or equal to 90% in 15 cases; greater than or equal to 80% in 3 cases) and left anterior hemiblock is indicative of left main coronary or proximal left anterior descending artery disease. In this series, medical therapy did not make exercise-induced left branch hemiblock regress, in contrast to aortocoronary bypass surgery and angioplasty.     

Mutation detection in 65 families with a possible diagnosis of ornithine carbamoyltransferase deficiency including 14 novel mutations

The high new mutation rate and the wide spectrum of mutations found in patients with ornithine carbamoyltransferase (OCT) deficiency means that direct mutation analysis is essential for providing accurate carrier detection and prenatal diagnosis in affected families. We present our strategy for mutation detection in the OCT gene and summarize the results from 31 families with a confirmed diagnosis and 34 families with a suspected diagnosis of OCT deficiency, and describe 14 previously unreported mutations.