Transoesophageal echocardiography in heart disease—old technologies, new tricks

Cardiac ultrasound and upper gastrointestinal endoscopy are relatively old technologies. With the introduction of new ultrasound probes and by incorporating ultrasound technology into conventional endoscopes, ‘new tricks’ in cardiac imaging were discovered. Posterior structures of the heart are now able to be imaged clearly by the ultrasound probe from the oesophagus. Consequently, better resolution of cardiac anatomy allows more accurate diagnosis of cardiac pathologies which is not possible using conventional transthoracic (TT) approach. Over a period of two years, 1200 cases of transoesophageal echocardiography (TOE) were undertaken in our institution. The major indications were diseases of the aorta (10%), source of cardioembolism (28%), assessment of native and prosthetic valve function (20%), suspected endocarditis and its complication (17%), pre and post percutaneous transluminal mitral valvotomy (PTMV [13%], congenital heart disease (2%) and others (10%). The greatest impact with TOE is in the diagnosis of aortic dissection and transection, TOE is superior to conventional TT approach in detecting potential source of embolism, valvular vegetations and its complication, native and prosthetic valve dysfunction and LA thrombus prior to PTMV. Observations by TOE such as spontaneous echo contrast (SEC) in the left atrium open new challenges for further research in its role in the pathogenesis of LA thrombus and its association with cardioembolic event. Other areas of interest include; reclassification of distal aortic dissection and the use of TOE in intra-operative work.     

In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain.

Metastasis (the spread of cancer from a primary tumor to secondary organs) is responsible for most cancer deaths. The ability to follow the fate of a population of tumor cells over time in an experimental animal would provide a powerful new way to monitor the metastatic process. Here we describe a magnetic resonance imaging (MRI) technique that permits the tracking of breast cancer cells in a mouse model of brain metastasis at the single-cell level. Cancer cells that were injected into the left ventricle of the mouse heart and then delivered to the brain were detectable on MR images. This allowed the visualization of the initial delivery and distribution of cells, as well as the growth of tumors from a subset of these cells within the whole intact brain volume. The ability to follow the metastatic process from the single-cell stage through metastatic growth, and to quantify and monitor the presence of solitary undivided cells will facilitate progress in understanding the mechanisms of brain metastasis and tumor dormancy, and the development of therapeutics to treat this disease.     

Quantification of naturally occurring benzodiazepine-like substances in human breast milk

The possible occurrence of benzodiazepine-like substances in human breast milk was investigated in 35 healthy, newly delivered women who were known not to be taking benzodiazepines. Maternal blood samples and a sample of breast milk were obtained on the fifth post partum day. A radioreceptor technique (lower limit of detection 1.5 ng/ml; difference between duplicates at various concentrations <7%) was used for measuring benzodiazepine-like substances in blood and breast milk (with and without prior extraction). No benzodiazepine-like substances could be demonstrated in any of the blood samples taken from the 35 women. Measurable concentrations of benzodiazepine-like substances were demonstrated in all but 1 of the 35 breast milk samples. The mean concentration of benzodiazepine-like substances for all 35 women was 4.3±2.3 ng/ml (range 0–9.3 ng/ml) expressed as lorazepam. The corresponding value for extracted breast milk was 2.6±1.5 ng/ml (range 0–7.0 ng/ml). There was no association between concentrations of benzodiazepine-like substances in breast milk and maternal age, weight, height and body mass or parity, or the sex of the infant and infant birth weight. We suggest that non-detectable amounts of benzodiazepine-like substances in serum are concentrated in the mammillary glands and excreted in a higher concentration in breast milk. It is less likely that the relevant benzodiazepines are produced in the mammillary glands.     

Studies on the molecular pharmacology of GR63178A. A novel pentacyclic pyrolloquinone anticancer drug.

GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs.     

Toxicity of the blue-green alga (cyanobacterium) Microcystis aeruginosa in drinking water to growing pigs,as an animal model for human injury and risk assessment

Hepatotoxins from blue-green algae are increasingly recognized as a potential hazard in drinking water supplies. The clinical consequences of ingestion include acute or chronic liver injury, with the possibility of enhanced susceptibility to, and growth of, liver tumors. To establish guidelines for water safety requires the demonstration of dose-dependent effects of toxicity and experimental determination of maximum “no-adverse-effect levels.” This paper describes the use of growing pigs as a model for human injury resulting from Microcystis toxins in drinking water. Risk assessment calculations using a series of safety factors are carried out, resulting in a guideline level after incorporating an additional safety factor for tumor promotion of approximately 1.0 μg toxins/L. With the Microcystis used for this trial, that concentration corresponds to 5000 cells/mL. © 1994 by John Wiley & Sons, Inc..