Oncogenes as mediators of cell growth and differentiation.
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Animals↗
Biomedical subjects
R M Lebovitz
Publications and source records attributed to R M Lebovitz.
Chemical carcinogens induce cadmium resistance and activate metallothionein genes in cadmium sensitive S49 mouse cells.
Treatment of cadmium-sensitive (Cds) metallothionein-negative S49 mouse cells with two direct-acting chemical carcinogens (N-ethylnitrosourea or N-acetoxy-2-acetylamino-fluorene) or with u.v. radiation induced a large increase in phenotypically stable cadmium-resistant (Cdr) variants. In contrast, treatment with any of three agents which alkylate proteins (N-ethylmaleimide, iodoacetate, or phenylmethyl-sulfonyl fluoride) was without effect. Similarly, treatment with 2-acetylaminofluorene (a pre-carcinogen) or with 12-O-tetradecanoylphorbol-13-acetate (a tumor promoter) did not result in an increase in Cdr variants. Initial studies indicate that in many variants the metallothionein-I gene, the metallothionein-II gene, or both have been activated. Thus the induction of cadmium resistance in Cds cells is a potentially useful system to explore the activation of quiescent genes by carcinogens.
Acetoxyacetylaminofluorene↗
Karsch-Neugebauer syndrome: split foot/split hand and congenital nystagmus.
A family with four members with split foot/split hand malformations and congenital nystagmus is described. The clinical characteristics in this family correspond to those seen in two other families previously reported. Taken together, these three families suggest that a single, pleiotropic dominant gene is causal. Karsch-Neugebauer syndrome is suggested as an appropriate eponymic designation for this disorder.
Abnormalities, Multiple↗
Familial recurrence of terminal transverse defects of the arm.
Three families in which relatives were concordant for upper limb terminal transverse defects are described. These families and previously reported ones with similar recurrence of terminal transverse defects are reviewed and analyzed. It is suggested that, at least in part, the patterns of relatedness for these recurrences more likely are the result of a genetic contribution to the development of this birth defect, rather than such recurrences being solely due to chance.
Adult↗
Delayed diagnosis in congenital adrenal hyperplasia. Need for newborn screening.
Medical records of all patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency who were followed up at the University of Wisconsin Hospitals, Madison, from 1956 to 1979, were reviewed to document the ages at diagnoses. Without newborn screening, the average age at diagnosis for 32 patients was 12.6 months (7.3 months for female infants and children and 22.7 months for male infants and children). In the newborn population, ambiguity was recognized in 15 of 21 female infants and in none of the male infants. Initial-appearing symptoms in female infants and children included ambiguous genitalia in 15 of 21, precocious puberty in four, and salt-losing crises in two. In the male infants and children, the reasons for diagnoses were salt-losing crises in seven of 11 and precocious puberty in four. These results indicate that in the absence of newborn screening, diagnosis is frequently delayed.
Adrenal Hyperplasia, Congenital↗
Germ cell degeneration in normal and microwave-irradiated rats: potential sperm production rates at different developmental steps in spermatogenesis.
Germ cell degeneration in 14 normal and 14 microwave-irradiated, adult (400-500 gm), Sprague-Dawley rats was compared by evaluating potential sperm production rates at different developmental steps in spermatogenesis. Following 9 days of irradiation at 1.3 GHz (6 hours/day at 6.3 mW/gm using 1-mu sec pulsewidth at 600 pulses/second) or sham treatment, rats were killed at 6.5, 13.0, 26.0, or 52.0 days following treatment. Testes were perfused with 2% glutaraldehyde, embedded in Epon, and sectioned at 0.5 micron for morphometric analyses. Plasma LH and FSH concentrations were determined by radioimmunoassay from blood collected on the day of death. Considering nuclear size, percentage of nuclei in the parenchyma, and life span of different cells, potential daily sperm production was determined for type B spermatogonia, preleptotene or pachytene primary spermatocytes, or spermatids with round nuclei. No differences (P greater than .05) in parameters tested were found among time periods following irradiation. With the possible exception of sperm production per testis (P less than .05) based on pachytene spermatocytes, microwave irradiation had no effect on the parameters evaluated. No degeneration was detected in spermatogenesis when potential sperm production rates were determined either from type B spermatogonia to spermatids or from type B spermatogonia to a posttesticular approximation of sperm production rate. Thus, it appears that regulation of sperm production rates must take place during spermatogonial mitoses, since once the number of type B spermatogonia is determined, there is essentially no subsequent alteration in sperm production potential in normal or irradiated adult rats.
Animals↗
Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei.
We have developed a procedure for preparing extracts from nuclei of human tissue culture cells that directs accurate transcription initiation in vitro from class II promoters. Conditions of extraction and assay have been optimized for maximum activity using the major late promoter of adenovirus 2. The extract also directs accurate transcription initiation from other adenovirus promoters and cellular promoters. The extract also directs accurate transcription initiation from class III promoters (tRNA and Ad 2 VA).
Animals↗
Testicular function of rats following exposure to microwave radiation.
Male Sprague-Dawley rats were exposed for 6 h per day for nine days to pulse-modulated microwave radiation (1.3 GHz, at 1-microseconds pulse width, 600 pulses per second). Exposures were carried out in cylindrical waveguide sections at a mean dose rate of 6.3 mW/g; sham controls were treated similarly and received no irradiation. At time periods corresponding to 0.5, 1.0, 2.0, and 4.0 cycles of the seminiferous epithelium, groups of four sham-irradiated and four irradiated rats were killed and the testes removed for analysis. Net mass of the testes, epididymides, and seminal vesicles; daily sperm production (DSP) per testis and per gram of testis; sperm morphology; and the number of epididymal sperm were determined. There were no statistically significant differences between the sham-irradiated and irradiated groups with respect to any measured variable. In a group of seven surrogate animals of similar body mass, the dose rate of 6.3 mW/g caused a net change in body temperature (via rectal probe) of 1.5 degrees C.
Animals↗
Pulse modulated and continuous wave microwave radiation yield equivalent changes in operant behavior of rodents.
Long-Evans rats were trained to the point of stable performance on a multicomponent (fixed-ratio, timeout) operant task. Different groups were exposed to continuous wave (CW) and to pulse modulated (PM) microwave radiation (MWR) during daily three-hour behavioral sessions. The rates of responding under actual and sham exposure conditions were noted. With comparable MWR dose rates, CW and PM MWR (5.8 and 6.7 mW/g, respectively) were equally effective in reducing response rates during both the fixed-ratio and the timeout components of the operant sessions. Dose rates of this order were associated with an elevation in body temperature of 0.5 to 1.0 degrees C. At 3.6 mW/g, whereas the mean rates of fixed-ratio responding were unchanged, the rates of responding during timeout were reduced significantly. Again, CW and PM MWR yielded essentially equivalent results. This MWR dose rate was not accompanied by a measurable increment in whole body temperature. It appears that (1) fixed-ratio operant responding of rats for food reward was more robust, that is, less subject to suppression by concurrent exposure to MWR than was bar-pressing during timeout, (2) PM and CW MWR, especially at the higher dose rate, effectively enhanced operant control over timeout responding and (3) the equivalent effects of CW and PM MWR support the hypothesis of a thermal basis for their effect despite the apparent inability to detect changes in whole body temperature.
Analysis of Variance↗
Two distinct central serotonin receptors with different physiological functions.
Two distinct serotonin (5-hydroxytryptamine) receptors designated serotonin 1 and serotonin 2 bind tritium-labeled serotonin and tritium-labeled spiroperidol, respectively. Drug potencies at serotonin 2 sites, but not at serotonin 1 sites, predict their effects on the "serotonin behavioral syndrome," indicating that serotonin 2 sites mediate these behaviors. The limited correlation of drug effects with regulation by guanine nucleotides suggests that serotonin 1 sites might be linked to adenylate cyclase. Drug specificities of serotonin-elicited synaptic inhibition and excitation may reflect serotonin 1 and serotonin 2 receptor interactions, respectively.
Adenylyl Cyclases↗
Prolonged microwave irradiation of rats: effects on concurrent operant behavior.
Two measures of performance were used to study the effects of pulse-modulated microwave radiation (PM MWR) on schedule-controlled operant behavior of rats: 1) cued (SD), fixed-ratio (FR) bar pressing for food reinforcement; and 2) noncued (Sd) bar pressing in the absence of food reinforcement. The animals were irradiated and the behavioral data were obtained concurrently, during daily three-hour sessions, five days per week for six to nine weeks. Each experiment began with a two to three-week baseline interval of sham irradiation; a two to three-week interval of sham irradiation followed the irradiation phase. The irradiated animals were exposed to 1.3-Ghz PM MWR (pulse width of 1 microsecond at 600 pulses per second) at whole-body, average specific absorbed-dose rates of from 1.5-6.7 m W/g. Control and irradiated animals were tested in identical, cylindrical waveguide exposure/behavioral assemblies; different groups of irradiated and sham-irradiated animals were used for each dose rate. At 1.5 mW/g, the levels of SD operant responding by control and irradiated animals were comparable, and showed similar progressive diminutions over the course of each daily session. Sd operant responding was more variable, but again comparable, with both groups showing similar, progressive declines in rate of responding during each session. At 3.6 mW/g, no specific effects on SD operant response rates were observed. However, there was an initial and transient increase in the rate of extinction of Sd responding. At 6.7 mW/g, SD response rates were slightly reduced, whereas there was a major reduction in noncued (Sd) operant responding followed by a sharp rebound during the first post-MWR week. This marked reduction in Sd operant responding at MWR onset was in contrast to the relative stability and persistence of FR responding for food reinforcement.
Animals↗
Computer-based operant behavioral system for microwave bioeffects research.
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Animals↗
Microwave irradiation and instrumental behavior in rats: unitized irradiation and behavioral evaluation facility.
A facility for the exposure of small animals to pulse-modulated microwave radiation (PM MWR) concurrent with their performance of operant behavioral tasks is described. The computer-managed facility comprises an array of 32 individual waveguide exposure cells, each enclosing instrumental conditioning apparatus within a plastic subhousing. The distribution of the microwave electric field intensity within the waveguide was measured by a nonperturbing probe and the modifications induced by the behavioral apparatus and animal within the waveguide determined. Input and interior voltage standing-wave ratios are presented to characterize the design of the chambers and to demonstrate the suitability of the chambers for whole-body irradiation of rat. The specific absorption rate (SAR) is presented utilizing data derived from incremental thermometric examination of saline loads and of selected sites in rat carcasses. This is compared with the whole-body SAR derived from the input/output energy balance equation for the waveguide. The results of continuous monitoring of the SAR by the latter method, while unrestrained rats were engaged in operant and exploratory behavior within the waveguide, are utilized to derive a relationship between chamber input power and the dose rate for adult rats behaviorally active within the waveguide. From these data, we conclude that the experimental array provides a practical method for exposing a large number of animals to PM MWR for long periods of time and coincident with the establishment and/or performance of complex operant behavior.
Animals↗
Autorhythmicity of spontaneous interictal spike discharge at hippocampal penicillin foci.
Penicillin-induced epileptogenic foci in the cat hippocampus show a marked tendency for brief but periodic seizure discharges known as 'interictal spikes' (IS). Here, each IS is shown to be followed by a marked elevation and subsequent slow fall-off of the focal seizure threshold. The time constant of this process approximates the spontaneous inter-IS interval and these two parameters appear to vary in concert. The timing of the IS train is always reset by interjected ISs but not by stimuli that are subthreshold for the IS. In sum, this modulation of focal excitability does not appear to be imposed by local or projected rhythmic activity other than that initiated by the IS itself. The firing patterns of the majority of observed hippocampal single units in the vicinity of the focus show a prolonged suppression of spontaneous firing for from 2 to 10 sec or more after each IS, independent of whether the IS was spontaneous or elicited. A smaller number of units show delayed, intense activation following each IS. Both of these forms of response appear to originate from large cells in and near the pyramidal cell body layer. Assuming that these single unit data represent a sampling of pyramidal cell discharge, then the prevalence of a prolonged post-IS pause suggests that the rhythmicity of spontaneous penicillin foci derives from an inhibitory phasing of the population based paroxysmal activity. The periodic spontaneous IS discharge can be viewed, therefore, as a locally regulated, autorhythmic process impressed upon the activity of the neuronal population by the development of a functional suppression of unit activity following each IS.
Animals↗
Expression of the autonomous parvovirus H1 genome: evidence for a single transcriptional unit and multiple spliced polyadenylated transcripts.
We identified viral transcripts in parvovirus H1-infected rodent cells using the S1 nuclease mapping technique of Berk and Sharp (1977, 1978). The most abundant viral transcript, present in both nucleus and cytoplasm, is approximately 2.8 kb long and represents about 56% of the viral genome. Less abundant viral transcripts of 3.0, 1.45 and 1.30 kb, and possibly other minor viral transcripts, are also detected in nuclear and cytoplasmic fractions. In contrast, a prominent 4.7 kb viral transcript which corresponds to 95% of the viral DNA is found only in the nucleus; this finding suggests that the parvovirus genome may function as a single transcription unit. Virus-infected cells pretreated with cycloheximide accumulate all these viral transcripts. Analyses of RNA-DNA hybrids (isolated from neutral agarose gels) by electrophoresis on alkaline agarose gels indicate that the 4.7, 3.0 and 2.8 kb viral transcripts are "spliced" RNAs. The nuclear-specific 4.7 kb transcript appears to be encoded by two noncontiguous DNA segments of 2.2 and 2.6 kb. The 3.0 and 2.8 kb transcripts are apparently encoded by.a 2.6 kb segment of DNA and one or more much smaller noncontiguous DNA segments, one of which is approximately 170 nucleotides long.
Animals↗
Serotonin receptor binding sites affected differentially by guanine nucleotides.
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Animals↗
Anatomic and pharmacologic differences between two types of aversive midbrain stimulation.
Chronic stimulating electrodes were implanted into two separate midbrain sites in rats. One site was the dorsal central gray area (DCG), where electrical stimulation produced frantic, escape-seeking behavior which grossly appeared fear-like and/or pain-like. The other site was in the ventral reticular formation (VRF), where stimulation produced a stereotyped circling response. Stimulation at both sites was aversive in that these animals would bar press for escape in a decremental bar-pressing paradigm. In this paradigm, each bar press decremented the current by five per cent of the initial current level. Following the acquisition of stable baseline decremental bar-pressing performance, animals were given injections of either the serotonin-depleting drug, para-chlorophenylalanine (PCPA), or the catecholamine-depleting drug, alpha-methyl-para-tyrosine (AMPT). Control animals received normal saline. Compared to saline control animals, PCPA-injected DCG-stimulated animals showed a marked increase in decremental bar pressing, whereas VRF-stimulated animals showed no change. AMPT-injected VRF-stimulated animals showed a marked decrease in decremental bar pressing, but the DCG-stimulated animals were not affected. These results suggest that escape behavior from electrical stimulation of midbrain sites is mediated by more than one neural system.
Animals↗
Serotonergic reduction of dorsal central gray area stimulation-produced aversion.
Stimulating electrodes were implanted into the dorsal central gray area (DCG) of rats. The animals were trained to bar press to decrement the aversive DCG stimulation current. Rats treated with 5-hydroxytryptophan (5-HTP), 75 mg/kg or 150 mg/kg, showed a dose-dependent reduction in decremental bar pressing. In a second study, animals received either chlorimipramine, 15 mg/kg, protriptyline, 15 mg/kg, or 5-HTP, 150 mg/kg. Chlorimipramine, a strong blocker of serotonin reuptake, and 5-HTP produced significant reductions in decremental bar pressing. Protriptyline, a weak serotonin reuptake blocker, produced no significant effect. These results suggest that serotonin reduces aversive neural mechanisms associated with the dorsal central gray area.
5-Hydroxytryptophan↗