Testicular cancer--case studies.
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Adult↗
Biomedical subjects
K Gordon
Publications and source records attributed to K Gordon.
Doses and population irradiation factors for Canadian radiation technologists (1978 to 1988).
Individual and collective radiation doses received by Canadian radiation technologists (RTs) working in diagnostic radiology, nuclear medicine and radiotherapy are summarized for the period 1978 to 1988. The data were obtained directly from the National Dose Registry, Department of National Health and Welfare. Over the 11-year study period the mean annual dose equivalent fluctuated around 0.2, 1.8 and 1.1 mSv for RTs working in diagnostic radiology, nuclear medicine and radiotherapy respectively. Over the same period the occupational collective dose equivalent decreased in diagnostic radiology (by 44%) and radiotherapy (by 35%) and increased in nuclear medicine (by 45%). Approximately 10,000 RTs are monitored each year, with an estimated total occupational collective dose equivalent of about 3.6 person-sieverts. Analysis of dose distribution data showed that only 1.3% of all monitored RTs received an annual whole-body dose equivalent greater than the current legal limit for members of the public (5 mSv). Approximately half of the RTs working in nuclear medicine and radiotherapy received an annual dose equivalent in excess of 0.5 mSv; only 7.3% of their diagnostic radiology counterparts exceeded this level. Demographic data showed a high preponderance of young women in all three RT classifications, and an analysis of the radiation risks to this occupational group revealed increases of up to 12% above the risk associated with a "standard" adult working population exposed to the same collective dose equivalent.
Adult↗
Methsuximide-induced movement disorder.
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Adolescent↗
Positive and negative control of translation by the leader sequence of cauliflower mosaic virus pregenomic 35S RNA.
We have studied the influence of the 600 nt long leader sequence of cauliflower mosaic virus 35S RNA on downstream translation. Plant protoplasts were transfected with plasmids expressing a CAT reporter gene from a mRNA, containing wild-type or mutant forms of the 35S RNA leader. Deletion analysis revealed the presence of three separate stimulatory sequence regions, S1, S2 and S3. The latter two interact with each other to enhance downstream translation 5- to 10-fold. This enhancement was not observed in protoplasts from a non-host plant. In the absence of either S2 or S3, the region I2, located in between, exerts an inhibitory effect on downstream translation, probably due to the presence of short open reading frames. Expression of a reporter gene inserted into I2 increases 2-fold upon deletion of either S2 or S3. We propose that mRNA regions S2 and S3 form a complex with cellular factors that allows scanning ribosomes to bypass region I2.
Base Sequence↗
Single dose long-term suppression of testosterone secretion by a gonadotropin-releasing hormone antagonist (Antide) in male monkeys.
This study was designed to find the minimal single dose of Antide (Nal-Lys GnRH antagonist) that would provide long-term inhibition of serum testosterone levels in adult male monkeys. At 3 mg/kg (sc), Antide blocked testosterone secretion for only a few days. However, when the dose of Antide was raised to 10 mg/kg, some of the males manifested testosterone inhibition lasting more than 60 days, while shorter durations of action were found in others. These preliminary findings increase our interest in studying Antide as a potential male contraceptive agent, when combined with androgen replacement therapy, as well as for therapeutic applications in men having prostatic carcinoma. Importantly, Antide lacks the sometimes deleterious "flare" effect known to occur when GnRH agonists are used to treat these patients.
Animals↗
Transient hypoxia alters striatal catecholamine metabolism in immature brain: an in vivo microdialysis study.
Microdialysis probes were inserted bilaterally into the striatum of 7-day-old rat pups (n = 30) to examine extracellular fluid levels of dopamine, its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). The dialysis samples were assayed by HPLC with electrochemical detection. Baseline levels, measured after a 2-h stabilization period, were as follows: dopamine, not detected; DOPAC, 617 +/- 33 fmol/min; HVA, 974 +/- 42 fmol/min; and 5-HIAA, 276 +/- 15 fmol/min. After a 40-min baseline sampling period, 12 animals were exposed to 8% oxygen for 120 min. Hypoxia produced marked reductions in the striatal extracellular fluid levels of both dopamine metabolites (p less than 0.001 by analysis of variance) and a more gradual and less prominent reduction in 5-HIAA levels (p less than 0.02 by analysis of variance), compared with controls (n = 12) sampled in room air. In the first hour after hypoxia, DOPAC and HVA levels rose quickly, whereas 5-HIAA levels remained suppressed. The magnitude of depolarization-evoked release of dopamine (elicited by infusion of potassium or veratrine through the microdialysis probes for 20 min) was evaluated in control and hypoxic animals. Depolarization-evoked dopamine efflux was considerably higher in hypoxic pups than in controls: hypoxic (n = 7), 257 +/- 32 fmol/min; control (n = 12), 75 +/- 14 fmol/min (p less than 0.001 by analysis of variance). These data demonstrate that a brief exposure to moderate hypoxia markedly disrupts striatal catecholamine metabolism in the immature rodent brain.
3,4-Dihydroxyphenylacetic Acid↗
"The rushes." A migraine variant with hallucinations of time.
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Adolescent↗
Extended presence of antide (Nal-Lys GnRH antagonist) in circulation: prolonged duration of gonadotropin inhibition may derive from antide binding to serum proteins.
Previous data from this laboratory revealed a rapid (-12h) and unexpectedly long (-30 days) inhibition of pituitary gonadotropin secretion after a single injection of Antide (Nal-Lys GnRH antagonist) in ovariectomized (OVX) monkeys. Although the apparent mechanism of action of Antide is competitive occupancy of GnRH receptors, the etiology of the prolonged action is unknown. Here, we report development of a radioreceptor assay to measure circulating Antide levels to determine the mechanism(s) of its long duration of action. Five long-term OVX monkeys were injected with Antide (3.0 mg/kg). Blood samples were collected daily for 30 days, and thereafter on alternate days until day 60. Following sc or iv Antide injection, peripheral luteinizing hormone (LH) levels declined from 281 +/- 19 ng/ml to 29 +/- 3 ng/ml within one day (P less than 0.05). LH levels slowly recovered to pretreatment levels within 35 +/- 7 days. Peripheral Antide levels were 16,531 +/- 4,432 ng/ml within 15 minutes following iv injection, and 52 +/- 21 ng/ml at 1 day after sc Antide injection. Interestingly, thereafter clearance of Antide-from the peripheral circulation was very slow, with an apparent t1/2 (second phase) of 6.5 days following iv administration. Detectable Antide levels were present in the peripheral circulation for more than one month in all five monkeys. In a second experiment, incubation of 125I-Tyro Antide with OVX monkey serum resulted in binding of the labelled peptide to serum proteins and reduction of 125I-Tyro Antide binding to pituitary receptors. Following gel permeation chromatography, greater than 70% of the radioactivity was associated with a 66 kDa protein(s). In conclusion, the prolonged duration of gonadotropin inhibition by Antide seems to derive from the long circulatory half-life of this molecule. In turn, this extended action of Antide may be manifest, at least in part, by binding to serum protein(s) that serves as a built-in peripheral depot release mechanism.
Animals↗
Diagnostic thyroid procedures and corresponding radiation doses in Manitoba: 1981-1985.
Data on nuclear medicine thyroid examinations performed in Manitoba (population 1 million) from 1981-1985 were collected, with more detailed demographic data obtained on 1,100 consecutive patients between June 1987 and January 1988. An average of 2,081 patients were examined per year, 81% female and 19% male, representing 8.4% of all nuclear medicine procedures. Typical administered activity and associated HE per patient were 238.0 MBq and 1.5 mSv for 99mTc, 7.4 MBq and 1.2 mSv for 123I, and 0.33 MBq and 3.9 mSv for 131I. Based on NCRP risk estimates with explicit corrections for age, sex, and radionuclide used, it is estimated that the rate of thyroid cancer induction is unlikely to exceed 0.56 y-1, of which about 10% would be fatal. This estimate is about a factor of 4 less than that generated using more generally applicable radiation protection risk estimates averaged over both sexes and all ages in the general population. The replacement of 131I with the present mix of radiotracers used for thyroid evaluation has resulted in a reduction of the estimated population detriment by a factor of 3.6.
Adolescent↗
A novel regimen of gonadotropin-releasing hormone (GnRH) antagonist plus pulsatile GnRH: controlled restoration of gonadotropin secretion and ovulation induction.
Using a primate model, we have tested a novel regimen of gonadotropin-releasing hormone (GnRH) antagonist plus pulsatile GnRH for the achievement of controlled restoration of gonadotropin secretion and ovulation induction. As a prelude, ovariectomized cynomolgus monkeys (n = 3) were treated with Antide ([N-Ac-D-Nal(2)1, D-pCl-Phe2, D-Pal(3)3, Lys(Nic)5, D-Lys(Nic)6, Lys(iPr)8, D-Ala10]-GnRH) (3 mg/kg per day) for 6 consecutive days. On the 7th day, pulsatile GnRH therapy was initiated in a 7 day-on: 7 day-off regimen for a total of four exposures. Next, four intact monkeys were given Antide to suppress ovarian function (estradiol less than 10 pg/mL) followed by pulsatile GnRH. In the ovariectomized monkeys, Antide-induced suppression of gonadotropin concentrations was reversed by the pulsatile GnRH so that follicle-stimulating hormone concentrations were completely normalized and luteinizing hormone concentrations were returned to within the lower range (+/- 2 SD) of the pretreatment mean. The abruptness of the onset or loss of gonadotropin secretion was precisely synchronized with the weekly on and off phases of the GnRH pulse regimen. In intact monkeys, ovarian steroid secretions were abruptly subdued and then successfully re-established by pulsatile GnRH in the face of sustained circulating levels of Antide. Thus, we conclude that our primate model of combination therapy, GnRH antagonist plus pulsatile GnRH, establishes the possibility of a new clinical treatment regimen for patients desiring relief from the sequelae of hyperandrogenemia (polycystic ovarian disease) and ovulatory dysfunction.
Animals↗
Sharps injuries.
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Accidents, Occupational↗
Cauliflower mosaic virus produces an aspartic proteinase to cleave its polyproteins.
Cauliflower mosaic virus (CaMV), a plant pararetrovirus, produces polyproteins from its adjacent genes for the coat protein (ORF IV) and for enzymatic functions (ORF V). The N-terminal domain of the latter gene includes a sequence showing homology to the active site of other retroviral and acid proteases. We have now shown that this domain does indeed produce a functional aspartic protease that can process both the polyproteins. Mutations in the putative active site abolished virus infectivity. In transient expression studies in protoplasts, the N-terminal domain of ORF V was able to free active CAT enzyme from a precursor containing an N-terminal fusion of a portion of ORF IV. The junction between the two domains of this artificial polyprotein comprised sequences from the ORF IV product that had previously been shown to include a proteolytic processing site. The protease mutants were not able to free active CAT enzyme from this precursor. Direct analysis of cleavage at the same site in the ORF IV product using proteins expressed in Escherichia coli revealed the expected products. In vitro translation of a synthetic transcript covering ORF V was used to study the autocatalytic cleavage of the ORF product. Pulse-chase experiments showed that the 80 kd initial translation product was processed to yield a N-terminal doublet of polypeptides of 22 and 20 kd apparent mol. wt, which cover the protease domain. The mutants in the active site were not processed.
Amino Acid Sequence↗
Differential inhibition of downstream gene expression by the cauliflower mosaic virus 35S RNA leader.
The effect of the 600 nucleotide-long CaMV 35S RNA 5' leader sequence on the expression of downstream genes was analyzed both in plant protoplasts and in vitro. For transient expression studies in protoplasts derived from host and nonhost plants, the bacterial chloramphenicol acetyl transferase (CAT) gene was fused to the initiation codon of ORF VII. The leader sequence reduced CAT expression two- to four-fold in protoplasts derived from three host species, but 10- to 50-fold in protoplasts derived from three different nonhost species. For in-vitro studies the 35S promoter was replaced by the SP6 promoter. The leader reduced in-vitro translation of SP6 transcripts approximately six-fold, indicating that at least part of the inhibition observed in protoplasts is directly due to the interference of the leader sequence with translation. Other steps in gene expression that may also be affected are discussed.
Chloramphenicol O-Acetyltransferase↗
Probing studies on multiple dose effects of antide (Nal-Lys) GnRH antagonist in ovariectomized monkeys.
This study was designed to extend evaluation of the long-acting effects of a "third generation" Antide (Nal-Lys) GnRH antagonist on gonadotropin secretion in ovariectomized (OVX) monkeys, with special attention to recrudescence of pituitary gonadotropin secretion after multiple dose treatments, as well as pituitary secretory responsiveness to GnRH. The duration of FSH/LH inhibition by Antide was dose-dependent, as well as being much longer than for Nal-Glu GnRHant; however, full recrudescence of gonadotropin secretion, albeit gradual, did occur. The acute LH secretory response to serial iv boluses of GnRH, in the face of GnRHant-induced suppression of gonadotropin secretion, was transiently accelerated and biologically active. Thereafter, the state of FSH/LH inhibition was resumed chronically. Thus, treatment with Antide produced profound long-term inhibition of tonic gonadotropin levels, yet hyper-responsiveness to exogenous GnRH administration was maintained throughout.
Animals↗
Nuclear medicine staff and patient doses in Manitoba (1981-1985).
The number of diagnostic in vivo nuclear medicine (NM) procedures in the Province of Manitoba (population 1 million) has been examined over the period 1981 to 1985. The annual number of procedures performed has remained relatively constant at about 25 per thousand population. The isotope 99mTc accounted for 86% of all the studies performed and the number of NM procedures per imaging system was approximately 1,300 per annum. The total number of NM operators in the province increased from 30 in 1981 to about 40 in 1985. The mean NM operator dose was reduced from 3.8 mSv to 2.5 mSv over this five-year period and the collective operator dose underwent a smaller reduction of 13% to about 100 person-mSv in 1985. The value of the mean patient effective dose equivalent (HE) was relatively constant at 5.2 mSv. The contribution of diagnostic NM procedures to the annual per caput population dose in Manitoba was 0.13 mSv. Three diagnostic procedures (brain, bone and cardiac) accounted for approximately 80% of the collective patient HE. Patient profiles (age, sex and medical history) were obtained for the patients undergoing these three procedures, which showed them to be atypical in comparison to a normal working population. These data suggested that the application of the International Commission on Radiological Protection risk factor of 1.65 X 10(-2) Sv-1 to this patient population would have significantly overestimated the expected radiation detriment.
Female↗
The leading sequence of caulimovirus large RNA can be folded into a large stem-loop structure.
The 600 nt long sequences preceeding the first large ORFs (ORF VII) of three caulimoviruses, although varying in primary sequence, can be folded into a large stem/loop structure centered around a conserved stretch of 36 nucleotides. Deletions of the conserved sequence delay symptom appearance considerably, but do not affect expression of a reporter gene in plant protoplasts. Another striking similarity between the leaders concerns the number and distribution of small open reading frames (sORF) they carry. Expression of two of these sORFs was tested by fusion of a reporter gene: both were expressed in plant protoplasts.
Base Sequence↗
The instability of a recombinant plasmid, caused by a prokaryotic-like promoter within the eukaryotic insert, can be alleviated by expression of antisense RNA.
A region of the cauliflower mosaic virus genome was found to direct the expression of a nucleic-acid-binding protein in Escherichia coli. This protein is apparently toxic for the bacteria and leads to a destabilization of plasmids containing that region. Antisense RNA was used to diminish the unwanted expression and to stabilize the respective recombinant plasmids. The approach described may prove useful in other cases where problems with cloning of eukaryotic DNA arise.
DNA Restriction Enzymes↗