Further studies on the increase in drug-metabolizing capacity adjacent to intrahepatic Morris hepatomas

Microsomal cytochrome P-450 content was higher in histologically non-tumorous liver adjacent to intrahepatically implanted Morris hepatomas 5123D or 7795 than in histologically normal liver far removed from each tumor. V_max values for microsomal benzo[a]pyrene monooxygenase activity and cyclophosphamide activation were also significantly higher in tumor-adjacent liver than in normal liver far removed from tumor. K_m values of these reactions were unchanged. After intrahepatic implantation, inert spheres of several different materials produced no regional differences in hepatic microsomal cytochrome P-450 content. Both intrahepatic Morris hepatomas exhibited markedly reduced cytochrome P-450 content and benzo[a]pyrene monooxygenase activity. Cyclophosphamide biotransformation could not be detected in microsomes from either Morris hepatoma. Similar recoveries from microsomes of far-removed and tumor-adjacent liver indicated that differences between these regions in drug-metabolizing activity could not be attributed to different stabilities or sedimenting properties of their microsomes. Although microsomal recovery was significantly less from hepatomas than from far-removed or tumor-adjacent liver, this loss of tumor microsomes accounted for only a small part of the reductions in cytochrome P-450-mediated monooxygenases observed within tumors. Compared to control rats. tumor-bearing rats exhibited no change in hepatic drug-metabolizing capacity measured in vivo by hexobarbital sleeping times and antipyrine elimination rates. Phenobarbital (PB) pretreatment of tumor-bearing rats induced cytochrome P-450 to different extents within far-removed liver, tumoradjacent liver, and both hepatomas. The same differential inducibility occurred with PB pretreatment for cyclophosphamide activation. After PB induction, differences in drug-metabolizing activity between far-removed and tumor-adjacent liver disappeared; though induced, these activities remained lower in the hepatomas than in other regions. These changes in drug-metabolizing activity in both basal and PB-induced states of various hepatic regions were related to changes in cellularity of tumor-adjacent tissue. Hepatocellular nuclei prepared from tumor-containing liver were separated into diploid and tetraploid classes by sucrose density gradient centrifugation. Compared to far-removed liver, tumoradjacent liver contained significantly more diploid nuclei and less tetraploid nuclei.     

Development of an optimal rechargeable cardiac pacemaker

While many rechargeable pacers, including a commercial unit have been developed using nickel-cadmium cells, they are in general limited by low cell capacity, short life without recharging, the need for frequent recharging, indirect monitoring of battery voltage by stimulation rate changes and gradually falling cell capacity with each cycle at body temperature.We have developed a low-drain rechargeable pacemaker, hermetically sealed in a seamless container, that will stimulate continuously for 4 yr without recharging. Our battery is a silver modified 1000 mA hr rechargeable version of the mercury-zinc cell proven by years of use in over 95% of pacers used clinically to date. It has functioned for over 6 yr in real time tests and in 120 accelerated tests has always simulated over 50 yr of pacing. Our pacer is small and thin, with less than one-half the displacement of current nonrechargeable units. Electromagnetic recharging energy is painlessly transmitted through the intact skin by a tuned coil, using a unique system unaffected by variations in implant depth. A telemetry oscillator permits noninvasive monitoring and telephone transmission of cell voltage, stimulation rate, implant depth, and optimal recharging coil location. Six animal and 3 clinical implants continue perfect function after up to 2.5 and 1 yr, respectively. A 6 yr life is proven and a greater than 20 yr life is anticipated.     

Observer reproducibility during computer-assisted planimetric measurements of nuclear features

To evaluate observer variance during microprocessor-assisted planimetry, nuclear features (area, perimeter, and form factor) were studied in a series of mammary ductal carcinomas. Fragments of formalin-fixed, paraffin-embedded tissue were re-embedded in plastic, sectioned at 1 micron, stained with methylene blue, and studied with a Zeiss-Kontron MOP-3 microprocessor-assisted planimeter. Both interobserver and intraobserver reproducibility were evaluated, the former among three different observers and the latter by two observers repeating their own measurements. Reproducibility was good for measurement of area, but deteriorated progressively for measurement of perimeter and form factor. Not only was observer correlation poor (identified via linear regression), but paired t-tests also showed consistent variation among observers. The major difficulty was in following the irregular nuclear contours that are characteristic of cancer cells. It is concluded that adequate demonstration of observer reproducibility remains an essential part of tissue investigation, even when the objective methods typical of morphometry are used.     

An algorithm for the control of nosocomial varicella-zoster virus infection

Inadvertent or uncontrolled introduction of varicella-zoster virus into the hospital environment occurs commonly and must be investigated in a systematic and efficient manner to minimize secondary spread to patients (particularly the immunocompromised) or hospital personnel. On the basis of a review of the literature and our practical experience with 11 such exposures to varicella-zoster virus during a 2-year period, we have developed a working algorithm for such investigations. Index cases most often are children, resident physicians, students, young nurses, and ancillary personnel, or adult patients with herpes zoster. A negative or uncertain past history of this infection is an unreliable predictor of susceptibility among the exposed and should be confirmed by serology tests or delayed hypersensitivity skin testing. An incubation-contagion timetable, coupled with a stratification of risk among the exposed, permits a prioritized response in dealing with an introduction of varicella-zoster virus. The preemployment screening of all hospital workers for susceptibility to varicella-zoster virus should be considered as a practical and cost effective policy.     

Effects of excess glucose and insulin on glycolytic metabolism during experimental myocardial ischemia

The selective metabolic effects of glucose and insulin were tested in an intact working swine heart preparation. Supplements of glucose (26.6 millimolar [mM] and insulin (0.025 units/ml) were provided to 18 hearts, 9 control hearts (coronary flow 151 ml/min) and 9 hearts rendered globally ischemic (coronary flow reduced from 167 to 85 ml/min). These hearts were compared with 14 additional hearts (6 control and 8 ischemic) given no supplements (glucose 8.6 mM, no excess insulin). In hearts without supplements, ischemia significantly decreased mechanical performance, myocardial oxygen consumption, fatty acid oxidation and tissue high energy phosphate stores. Glucose consumption was reduced from 133 micromoles (μmol)/hr per g (before ischemia) to 58 μmol/hr per g (P < 0.05), presumably from inhibition at glyceraldehyde-3-phosphate dehydrogenase. Data for control hearts with excess glucose and insulin were similar to data in control hearts without supplements except that glucose consumption and glycolytic flux were increased. Ischemia in treated hearts, as compared with untreated ischemic hearts, effected similar significant decreases in myocardial oxygen consumption, fatty acid oxidation and high energy phosphate stores and resulted in greater reductions in mechanical performance and in 10 minutes' less average survival time. Glucose consumption was reduced from 483 (before ischemia) to 242 μmol/hr per g (P < 0.005) and inhibition at glyceraldehyde-3-phosphate dehydrogenase was again noted. Thus, excess carbohydrate and insulin hormone, when infused directly into the ischemic myocardium, did not provide an efficacious increase in either glycolytic flux or energy production. These findings suggest that an alternative explanation for the reported efficacy of glucose-insulin-potassium infusions must be sought.     

The detection of unipolar and bipolar cardiac electrograms with a movable coaxial electrode

To define the effects of endocardial positioning on the sensing electrode's ability to detect the cardiac electrogram, a specially designed coaxial lead system with a movable, large surface area (50 mm²) proximal ring electrode and a small surface area distal tip electrode was placed transvenously in 17 mongrel dogs. When the sensing ring electrode was used in a unipolar mode, there were slight but insignificant decreases in R-wave amplitude while the ring remained in the ventricle. When the electrode was moved out through the valve into the atria there was a marked decrease in R-wave sensing, however, this was accompanied by a significant increase in P-wave amplitude. When the ring electrode was used in conjunction with the tip as a conventional bipolar system, the sensed R wave remained at uniformly high levels except when the two electrodes were very close together at the tip. P-wave amplitudes were not detected in the bipolar mode until the ring entered the atria.