Biomedical subjects
L Harris
Publications and source records attributed to L Harris.
Evidence that covalent complex formation between BCNU-treated oligonucleotides and E. coli alkyltransferases requires the O6-alkylguanine function.
Chloroethylnitrosoureas (CENUs) are thought to induce cytotoxic DNA interstrand cross-links via an initial reaction at O6-position of guanine, yielding a rearranged intermediate, O6,N1-ethanoguanine. Repair of these adducts by mammalian and bacterial DNA alkyltransferases blocks the formation of cross-links. Human alkyltransferase can form a covalent complex with DNA containing BCNU-induced cross-link precursors, but the nature of the DNA-protein linkage remains unknown. Using E. coli alkyltransferases expressed by the ada and ogt genes, we now demonstrate that both enzymes can form such complexes with CENU-treated DNA. We attribute this reaction to the O6-alkylguanine repair function, because an N-terminal fragment of the ada protein, which has only alkylphosphotriester repair activity, failed to form a similar complex. This result is consistent with the idea that complex formation requires an alkyltransferase reaction with a guanine adduct, such as O6,N1-ethanoguanine. It tends to exclude the possibility that such reactions simply involve alkylation of the enzyme by reactive DNA adducts such as chloroethylphosphate or chloroethylguanine.
A comparison between hemogram data as measured by technical and non-technical personnel using the QBC II.
Diagnostic testing is becoming relatively common practice in small laboratories associated with physicians' offices. Often the test that can be performed in this setting are limited to those that use relatively inexpensive equipment that can be operated by personnel who are not trained laboratorians. The QBC II is an instrument that has been promoted as a semiautomated instrument that is particularly appropriate in this setting. This study addressed the question of comparability of data produced by technical and non-technical operators.
Effects of cadmium and mercury on Na(+)-K+, ATPase and uptake of 3H-dopamine in rat brain synaptosomes.
Effects in vivo of cadmium (Cd), mercury (Hg) and methylmercury (CH3Hg) on Na(+)-K+ ATPase and uptake of 3H-dopamine (DA) in rat brain synaptosomes were studied. These heavy metals significantly inhibited the Na(+)-K+ ATPase activity in a dose-dependent manner. Similarly, inhibition of DA uptake by synaptosomes was also observed in rats treated with these metals. Intraperitoneal route of metal administration was found to be more effective than per os treatment. Mercuric compounds compared to Cd elicited a higher inhibition of Na(+)-K+ ATPase and DA uptake in rat brain synaptosomes.
High dose caffeine and ventricular arrhythmias.
The effect of high dose caffeine on ventricular arrhythmias was examined in 35 patients with recent myocardial infarctions. All patients received caffeine 450 mg or placebo on separate days using a randomized double-blind study design. Continuous Holter electrocardiographic recordings were performed for 8 h. Caffeine ingestion did not cause any increase in the frequency or complexity of ventricular ectopy with 19 of 35 patients experiencing ventricular arrhythmias after caffeine compared with 24 of 35 with placebo. Serious ventricular ectopic activity (including ventricular couplets and tachycardia) was similar on both study days. Moderately high doses of caffeine do not appear to increase ventricular arrhythmias in this patient population with ischemic heart disease.
Drugs of abuse: chemistry, pharmacology, immunology, and AIDS. Summary of recommendations for future research.
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Attitudes to environment.
An opinion survey covering 16 countries, both developing and developed, revealed widespread concern about environmental deterioration. Many people felt that more should be done to reverse present trends, even if this meant forgoing some material gains.
Transatrial balloon technique for activation mapping during operations for recurrent ventricular tachycardia.
Results of operations for recurrent ventricular tachycardia have improved since methods of mapping that allow a directed approach to the problem have been developed. With standard operative techniques (ventriculotomy and introduction of a hand-held probe or multiple electrode array), it has not always been possible to obtain satisfactory endocardial activation maps during the tachycardia. We have recently developed a new transatrial balloon approach that has greatly facilitated intraoperative mapping. This paper describes our total experience with the new approach and draws attention to details of the cardiopulmonary bypass technique and the surgical approach needed for safe balloon insertion across the mitral valve. We describe how correlation between position of target electrodes on the balloon and the internal geometry of the heart is achieved and discuss the choice and application of appropriate ablation techniques. In our series of 37 consecutive patients, 35% had a grade IV ventricle (ejection fraction less than 20%), 32% had a previous posterior infarct, 51% did not have a resectable aneurysm, and 54% had been receiving amiodarone within 1 month of the operation. These factors have been associated with poor operative results in other series. With the transatrial balloon technique, we were able to induce and map ventricular tachycardia in 100% of patients (average 2.6 +/- 1.3 morphologies per patient). Using a variety of ablation techniques (endocardial excision, cryoablation, or balloon electric shock ablation), we have achieved surgical control of the arrhythmias in 84% of patients with an operative mortality rate of 14%. We recommend transatrial balloon mapping as the procedure of choice for intraoperative identification of arrhythmogenic foci in patients with recurrent ventricular tachycardia.
Checking up on environmental health.
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Mapping of OGT in the E.coli chromosome.
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Scintigraphic differentiation of congenital soft-tissue extremity enlargement with Tc-99m DTPA.
Radionuclide imaging of benign soft-tissue tumors sometimes associated with extremity enlargement (7 patients) and/or osteodysplasia (6 patients) has demonstrated, in a total of 18 patients, several differentiating patterns of accumulation of Technetium-99m diethylene triamine pentaacetic acid (Tc-99m DTPA). Early imaging (within 15 min) as well as later imaging (one-half hour to 3 hours following the intravenous injection of the radiopharmaceutical) has shown that fatty tumors (lipomas, lipoblastomas, fibrofatty tissue) do not concentrate the isotope. Neurofibromas display gradual intensification of their radioactive content, while hemangiomas differ in their scintigraphic pattern depending on their histologic composition. Purely capillary hemangiomas have transient early intense activity while purely cavernous hemangiomas display no early activity but are well visualized on delayed scintigraphic images. Mixed hemangiomas display combined imaging characteristics of both capillary and cavernous types with the predominant pattern dependent upon the predominant histology. Aggressive fibromatosis exhibited an early fleeting display of intense radioactivity.
Monozygotic twins concordant for the narcoleptic syndrome.
We report the first documented monozygotic twins who both had the narcoleptic syndrome. We assessed monozygosity by HLA antigens and by blood groups. In contrast to virtually all other narcoleptics, they had HLA-DQ1 instead of HLA-DR2; this helped to localize the gene, and perhaps explains its greater expressivity in these than in other twins.
Bedside manners. Advice on how to deal with difficult patients.
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Inverse relationship between epidermal growth factor induced proliferation and expression of high affinity surface epidermal growth factor receptors in rat hepatocytes.
Rat hepatocytes express large numbers of high and low affinity surface membrane receptors (EGFR) for epidermal growth factor (EGF) but the roles of EGF and EGFRs in hepatocyte proliferation in vivo are unclear. F344 rat hepatocytes in primary culture proliferated maximally in response to continuous serum-free culture with 3.3 nM (20 ng/ml) EGF, as quantified by cumulative [3H]thymidine labeling index. However, serum concentrations of EGF in rats with normal livers or induced hepatocyte proliferation due to partial hepatectomy, carbon tetrachloride-induced necrosis, or hepatic neoplasia were consistently below 0.1 nM. The 3- or 6-hour pulse exposures to EGF (1.7 nM) between 0 to 16 hours had minimal effect on labeling index at 48 hours, but these pulse exposures at 24 or 32 hours were equivalent to continuous exposure. At 24 and 32 hours, the total specific surface binding of [125I]EGF to hepatocytes cultured free of EGF decreased to 43 and 24% of the initial values, respectively. Scatchard analysis of EGF binding indicated that hepatocytes lost all high affinity EGFRs (Kd of 0.08 nM) by 24 hours. Low affinity [125I]EGF binding at 0 hour (Kd 0.8 nM) was further reduced at 24 hours (Kd = 3.9 nM) and corresponded more closely to mitogenic concentrations of EGF in culture. These studies demonstrate that proliferative responsiveness of hepatocytes to EGF increases during culture by a process that involves prior loss of constitutive high affinity EGFRs. These results suggest that constitutive high affinity EGFRs do not elicit the proliferative response to EGF.
Protective value of a liver initiation-promotion regimen against the lethal effect of carbon tetrachloride in rats.
This study was designed as one test of the hypothesis that an early sequence of steps in hepatocarcinogenesis in the rat, with the production of hepatocyte nodules, may be a special form of adaptive response that has survival value for the host. Fischer 344 rats were initiated with a single dose of diethylnitrosamine. Hepatocyte nodules were rapidly generated by selecting for resistant hepatocytes by a brief exposure to 2-acetylaminofluorene coupled with partial hepatectomy, a procedure that leads to liver cancer without any further treatment. Most animals with hepatocyte nodules were completely resistant to single doses of CCl4 that induced 100% mortality in control animals. The demonstration of this protective effect is consistent with the proposed hypothesis.
Balloon electric shock ablation. Effects on ventricular structure, function, and electrophysiology.
We have recently developed a transatrial balloon approach for intraoperative endocardial mapping of ventricular tachycardia, which can be performed in the intact ventricle. In selected patients, we have eliminated the arrhythmia by passing a series of electric currents through specific beads on the balloon array. The goal of this new technique, balloon electric shock ablation, is to create a homogenous scar in the subendocardial target area identified by mapping. Experimental data exist on the effects of catheter delivery of electric discharges to the myocardium, but no data are available on the effects of balloon electric shock ablation. We have performed balloon electric shock ablation in animals (nine cathodal shocks of 100 J given through a 4 cm2 electrode grid). Ventricular function was assessed at 6 weeks and compared with function after a simple ventriculotomy and with function in control animals having no operation. Gated nuclear ventriculograms were obtained during volume loading. Myocardial performance and diastolic pressure volume relationships were determined for the three groups. After balloon electric shock ablation or ventriculotomy, left atrial pressures were increased at similar end-diastolic volumes, which indicated decreased ventricular compliance. The trend reached statistical significance (compared with data from control animals) only in the group undergoing balloon electric shock ablation. Myocardial performance (stroke work index/end-diastolic volume relationship) was unchanged in the three groups. In the long-term balloon electric shock ablation preparation, an electrophysiologic study (including burst pacing) failed to induce ventricular arrhythmias. At 6 weeks, the lesion created by balloon electric shock ablation was a layer of homogenous mature scar with sharply defined borders. There was no evidence of additional injury to the surrounding myocardium or to the mitral valve apparatus. These studies show that delivery of a series of electric shocks through a 1 cm balloon grid of electrodes can create an area of homogeneous, electrically inert scar and that this procedure when performed in healthy dog hearts has no significant effect on the structure and function of the rest of the left ventricle.
Terminal care: breaking bad news.
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