PLASMA PHOSPHOLIPASE A2 ACTIVITY IN CLINICAL ACUTE MYOCARDIAL INFARCTION

1. Phospholipase A2 (PLA2) cleaves phospholipids to produce a lyso-phospholipid and free fatty acid and, in view of the biological activity of the products, PLA2 may play a role in many disease states. Lyso-phospholipids and free arachidonic acid increase in ischaemic myocardium, indicating that ischaemia activates the enzyme. 2. Plasma PLA2 activity was measured in patients with acute myocardial infarction, based on the release of labelled arachidonic acid from Escherichia coli cell membrane. Fourteen males (peak serum creatine phosphokinase (CK) above twice upper normal) were studied on day 1 (within 6 h of chest pain onset), days 2-4, and days 6-9. Normal age matched males (n = 13) were also studied. 3. Plasma PLA2 in patients with uncomplicated myocardial infarction (n = 12) was, initially, 1.14 +/- 0.10 (s.e.m.) nmol/min per mL plasma, similar to that in the normal group (1.52 +/- 0.14). On days 2-4, PLA2 activity increased to 1.94 +/- 0.18 (P less than 0.001) and this activity was correlated with the earlier peak CK level (P less than 0.02). On days 6-9, PLA2 activity was 1.49 +/- 0.13 while in two patients who developed complications and underwent open-heart surgery between the last two measurements, there were further increases to 4.22 and 4.04 nmol/min per mL. 4. The increase in plasma PLA2 in uncomplicated myocardial infarction is likely to be due to release from the damaged myocardium; whether it contributes to pathophysiology is uncertain.     

Fentanyl and the interleukin-6 response to surgery

It has been suggested that large doses of opioids may suppress the interleukin-6 response to surgery. We examined the effects of the supplementation of inhalational anaesthesia with either 3 or 15 μg.kg⁻¹ fentanyl on the circulating interleukin-6, interleukin-8, C-reactive protein, cortisol and glucose concentrations in 16 patients undergoing pelvic surgery. In both groups, surgery evoked the expected glucose, cortisol and interleukin-6 response but no increase in interleukin-8 was detected. There were no significant differences between the two groups. We conclude that the supplementation of inhalational anaesthesia with conventional doses of opioids does not modify the cytokine response to surgery.     

Serum antibody responses in mice to intermittent inhalation of ovalbumin dust

Serum antibody production and induction of antibody tolerance were monitored in mice following intermittent inhalation of ovalbumin dust (mass concentration = 4.2 mg m-3; diameter of 80% of particles less than 2.6 microns). Repeated inhalation of microgram quantities of dust stimulated serum antibody production and development of tolerance. The sequence of these responses is analogous to that following oral presentation of antigen, but is produced by a much lower dose when antigen is presented via the respiratory tract.     

Novel antagonists of the 5-HT3 receptor. Synthesis and structure-activity relationships of (2-alkoxybenzoyl)ureas.

A series of benzoylureas derived from bicycle amines were prepared and evaluated for 5-HT3 antagonist activity on the rat isolated vagus nerve. From among these compounds, those analogues which were ortho substituted by an alkoxy group on the benzoyl function were shown to be potent 5-HT3 antagonists with similar or greater potency than the standard agent ondansetron. NMR and X-ray crystallography studies showed these o-alkoxy compounds to exist as a planar, hydrogen-bonded, tricyclic ring system. In molecular modeling studies on endo-N-[[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl-amino] carbonyl]-2-(cyclopropylmethoxy)benzamide (30) the central hydrogen-bonded ring was able to mimic an aromatic ring present in previously reported 5-HT3 antagonists.     

Measurement of degraded fecal hemoglobin-heme to estimate gastrointestinal site of occult bleeding appraisal of its clinical utility

Hemoglobin-heme is variably converted to porphyrin during enterocolic transit. This intestinal converted fraction, as measured by HemoQuant, was elevated as a predictor of the occult bleeding site in 152 patients with discrete lesions. The intestinal converted fraction, expressed as the percentage of total fecal hemoglobin, was similar with upper gastrointestinal and proximal colon lesions. Within the colon, values trended downward with more distal location: means ± standard deviations were 18±14 proximal colon, 16 ±15 sigmoid, and 10±10 rectum. The amount of fecal blood also affected the intestinal converted fraction; correcting for hemoglobin concentration improved separation by site. Corrected intestinal converted fraction values were significantly lower with rectal (P< 0.0005) and sigmoid (P<0.02) lesions than with proximal colon lesions. Unfortunately, large within-site variation caused considerable overlap between sites. We conclude that the intestinal converted fraction is influenced by the site and amount of bleeding. However, its clinical utility is compromised by substantial individual differences in luminal hemoglobin metabolism.Presented in part at the Annual meeting of the American Gastroenterological Association in San Francisco in May of 1986 (Gastroenterology 90:1431, 1986).Supported by the Mayo Foundation.     

Biochemical characterization of patients and prenatal diagnosis of sialic acid storage disease for three families

Summary Modifications of the assay method of Aminoff (1961) for the determination of sialic acid levels in urine, amniotic fluid, cultured cell homogenates and tissue homogenates, which reduce the interference from proteins by precipitation and from interfering chromogens by second derivative spectroscopy are described.Biochemical profiles of patients from three families with different clinical forms of sialic acid storage disease were made using data obtained with the new method. A family with two patients with the clinically severe, early-onset form is described, in which a 9-fold elevation of sialic acid can be detected in the skin fibroblasts and a 12-fold elevation in the urine. A patient from the second family is described with very severe clinical features and with 160-fold and 16-fold elevations of sialic acid in the urine and skin fibroblasts respectively. A patient from a third family is described with mild clinical features but with a 160-fold and 6-fold elevation of sialic acid in urine and skin fibroblasts respectively. The data obtained in this study are compared with data obtained in other laboratories on other patients.The method was used to assess the levels of sialic acid present in amniotic cells and chorionic villus cells obtained prenatally from pregnancies in each of the three families. In one case, in which amniotic cells were elevated in sialic acid and were vacuolated, the pregnancy was terminated. Follow-up studies confirmed the diagnosis. Pregnancies from the other two families were assessed to be not affected.