TWENTY YEARS' EXPERIENCE OF MYOCARDIAL INFARCTION: THE VALUE OF A HEART ATTACK REGISTER

SUMMARY Registers of disease serve a multitude of purposes, but are of particular importance to those interested in audit, in monitoring the introduction of new treatment or training programmes, in health service research, and in the planning of hospital services. The Nottingham Heart Attack Register has been in operation since 1973 and is proving to be an important data source. We present a brief history of the Register, describe how to set up a disease register and demonstrate how it can be of value to a wide range of health service staff using examples from our experience.     

Differential behavioral response in LEW/N and F344/N rats: effects of corticotropin releasing hormone.

1. Previous studies have documented that LEW/N rats exhibit an inflammatory response when challenged with a variety of stressful stimuli while histocompatible F344/N rats do not. These differences are thought to be regulated by the HPA axis. 2. In order to examine behavioral correlates of suspected differences in HPA activity in these strains, the baseline response to an open field as well as the effects of 3 micrograms/rat of CRH i.c.v. were compared across strains. 3. Significant differences in the pattern of activity in the open field, rearing, and grooming, as well as effects of CRH were found between strains. 4. The differences found are consistent with the notion that differences in endogenous CRH may form the basis for the differential susceptibility of these strains to autoimmune disease, and provide a model to study genetic determinants of CNS-immune system interactions.     

Cocaine-induced conditioned taste aversions: comparisons between effects in LEW/N and F344/N rat strains

Recent studies have found the LEW/N rat self-administers drugs of abuse at higher rates than the F344/N rat, suggesting a genetic predisposition toward the abuse potential of drugs. The current study compared the acquisition of a conditioned taste aversion (CTA) to cocaine in these strains. During an initial 20-min daily session a 0.1% saccharin solution was available and a dose (0–50 mg/kg, SC) of cocaine was given immediately after that session. Water was available during sessions on the following 3 days. Fluid consumption was assessed over three saccharin/water cycles, and a final saccharin session. Vehicle injections (0 mg/kg) that followed exposure to saccharin had no effect on subsequent saccharin consumption. In contrast, when cocaine followed exposure to saccharin, rates of saccharin consumption decreased over successive saccharin sessions in a dose-related manner in both strains. The lowest dose (18 mg/kg) decreased consumption in LEW/N rats but not in F344/N rats. An intermediate dose (32 mg/kg) decreased consumption maximally in LEW/N rats and only marginally in F344/N rats. The highest dose (50 mg/kg) decreased consumption completely in LEW/N rats and almost completely in F344/N rats. These findings demonstrate that significant differences in sensitivity to stimuli paired with cocaine occur between these strains. These differences are consistent with previous reports that the LEW/N rat is uniquely sensitive to both behavioral and biochemical effects of drugs of abuse. The current report extends this sensitivity to the noxious effects of these drugs. To the extent that noxious and reinforcing effects of cocaine are unrelated, these results suggest that the LEW/N rat does not exhibit a genetic predisposition to factors related only to the abuse potential of drugs.     

Lactoferrin decreases monocyte-induced fibroblast production of myeloid colony-stimulating activity by suppressing monocyte release of interleukin-1

Lactoferrin (Lf) is a negative regulator of myelopoiesis which operates by suppressing the release from mononuclear phagocytes of GM colony- stimulating factor (GM-CSF) or monokines which can then induce the release of GM-CSA from accessory cells. In this study, endotoxin- depleted, purified iron-saturated human Lf was assessed for its effect on the production of interleukin-1 by cultured monocytes and their subsequent effect on colony-stimulating factor release from cultured fibroblasts. Monocytes were grown with or without Lf and Lf that had previously been incubated with monoclonal anti-Lf. The monocyte- conditioned medium was then either assayed for the presence of interleukin-1 (IL-1) with an enzyme-linked immunosorbent assay or for its ability to stimulate fibroblasts to release growth factors for CFU- GM, BFU-E, or CFU-Mix colonies. In the presence of Lf (10(-7) or 10(-8) mol/L), GM colony-stimulating activity (GM-CSA) was suppressed by 31% to 73%, whereas stimulating activities for BFU-E and CFU-mix colony formation were suppressed by 93% to 100%. Antibody to Lf completely abrogated the suppressive effects observed with Lf, whereas antibody to IL-1 ablated the induction by monocyte-conditioned medium of CSA release by fibroblasts. Lf at 10(-7) and 10(-8) mol/L also reduced IL-1 synthesis by cultured monocytes from 60% to 77%. The inhibitory effects of Lf were only observed when Lf was added before adherence of the monocytes for culture. If Lf was added at the time of adherence or after adherence, no suppression was observed. We conclude that the inhibition of GM-CSA production/release by Lf is mediated through inhibition of the synthesis/release of IL-1 by mononuclear phagocytes. This inhibition of IL-1 prevents accessory cells from producing and/or releasing GM-CSA.     

A New Sock Electrode for Recording Epicardial Activation from the Human Heart: One Size Fits All

Simultaneous recording of epicardial activation from multiple sites during open heart surgery is essential for studying unstable ventricular arrhythmias. A previously described sock electrode array for this purpose requires custom-woven nylon sock material and expensive machined button electrodes. The limited compiiance and elasticity of nylon requires that a new sock be individually fitted for each heart. Despite careful fitting, 17–20% of electrodes do not make satisfactory epicardial contact in dogs. Further, electrodes frequently dislodge from the sock and wires break at the button electrode solder joint. Recognizing these limitations, we formed a new sock from Xspan* tubular dressing material and devised electrodes that attach securely to the sock. In six dogs. 90%± 3% of electrodes made satisfactory contact using the same Xspan* sock. significantly (p < .01) more than with the nylon sock despite far less labor. The same size X span* sock with 60 snap electrodes was used to record from 27 human hearts of widely different dimensions. Satisfactory epicardial contact was obtained in 90%± 14% of electrodes in the 18 patients with Wolff-Parkinson-White syndrome (WPW) and 75%± 15% of electrodes in the nine patients with coronary artery disease. In no case did an accessory pathway fail to conduct following sock placement. The hemodynamic effect of the Xspan* sock was evaluated in four dogs and was found to be minimal. Both the Xspan* sock and the snap electrodes are easily made from inexpensive, readily available materials. The same Xspan* sock accommodates o wide range of heart sizes, and the electrodes supported by the Xspan* sock record significantly better and with less dislodgement and wire breakage than previous socks.     

Development of a retroviral construct containing a human mutated dihydrofolate reductase cDNA for hematopoietic stem cell transduction

A double-copy Moloney leukemia virus-based retroviral construct containing both the NeoR gene and a mutant human dihydrofolate reductase (DHFR) cDNA (Ser31 mutant) was used to transduce NIH 3T3 and mouse bone marrow (BM) progenitor cells. This resulted in increased resistance of these cells to methotrexate (MTX). The transduced BM progenitor cells were returned to lethally irradiated mice. The recipients transplanted with marrow cells infected with the recombinant virus showed protection from lethal MTX toxicity as compared with mock- infected animals. Evidence for integration of the proviral DNA was obtained by amplification of proviral DNA by polymerase chain reaction (PCR) and Southern analysis. Sequencing a portion of the PCR-amplified human DHFR cDNA showed the presence of the mutation. These studies with the human Ser31 mutant DHFR cDNA gave results comparable with those obtained with the mutant murine DHFR cDNA (Leu to Arg22) in developing MTX-resistant BM. The Ser31 mutant human DHFR cDNA is currently being tested for infection of human CD34+ human BM and peripheral blood stem cells in vitro.     

Cardiovascular and Adrenal Proliferative Lesions in Fischer 344 Rats Induced by Long-term Treatment with Type III Phosphodiesterase Inhibitors (Positive Inotropic Agents), Isomazole and Indolidan

Male and female Fischer 344 rats were treated with the positiveinotropic agents, isomazole or indolidan, in the diet for 104weeks. The doses were 0.0, 11.5, 23.5, or 48.0 mg\kg and 0.0,0.12, 0.40, or 1.3 mg\kg, respectively. Only 17% of the malestreated with 48.0 mg\kg isomazole survived the duration of thestudy. The male component of the indolidan study was terminatedat 22 months, with only 18% of the high-dose males surviving.Sixty-five percent of the males treated with 48.0 mg\kg isomazoleand 70% of the males treated with 1.3 mg\kg indolidan were foundto have severe periarteritis, often with thrombi located mainlyin the mesenteric arteries. Fifty-four percent of the male ratstreated with 48.0 mg\kg isomazole and 55% of the male rats treatedwith 1.3 mg\kg indolidan died from cardiovascular disease comparedto 1–2% among the control males. Animals in the low- andmiddle-dose groups of both studies had a lower incidence ofcardiovascular disease than did those in the high-dose group.Additional lesions associated with the long-term administrationof both drugs were markedly increased incidence of adrenal medullaryproliferative lesions (both hyperplasia and pheochromocytomas)and increased incidence of chronic progressive glomerulonephrosis.These lesions, like those in the cardiovascular system, occurredin a dose-dependent manner and were more frequent in males thanin females. Treatment-related effects in these studies werejudged to be related to the pharmacologic action of these compounds.